Inhibitors of the wnt/beta-catenin pathway

ABSTRACT

The present disclosure relates to compounds that are capable of modulating the WNT/Beta-Catenin pathway. The disclosure further relates to methods of treating colorectal cancer and other WNT/Beta-Catenin mediated cancers.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/623,976, filed Jan. 30, 2018, the contents of which are fullyincorporated by reference herein

BACKGROUND

The Wnt-β-catenin signaling pathway plays a critical role indevelopment, stem cell self-renewal, and oncogenesis. The Wnt/β-cateninsignaling pathway has been found to be associated with various types ofhuman cancers, most notably colorectal cancers (CRCs) due to adenomatouspolyposis coli (APC) and CTNNB1 (β-catenin) mutations (Bienz, M. &Clevers, H. Cell 103, 311-320 (2000); Nature 487, 330-337, 2012);Fearon, E. R. & Vogelstein, B. Cell, 61, 759-767 (1990). However, noapproved drugs are available in the clinic for treatment of thesecancers via the targeting of the Wnt signaling pathway, despitesubstantial effort invested into therapeutic development of Wntinhibitors in the past two decades (Novellasdemunt, L., Antas, P. & Li,V. S. Am J Physiol Cell Physiol 309, C511-521, 2015; Nusse, R. &Clevers, H. Cell 169, 985-999, 2017). Thus, an unmet need exists forinhibitors of β-catenin.

SUMMARY OF THE INVENTION

In certain aspects, the present disclosure provides compound of FormulaI, Formula II, or Formula III:

or a pharmaceutically acceptable salt thereof, wherein,

-   X is C═O, NR³, C═NR³, S, S═O, S(═O)₂, or C═S;-   Y is heteroaryl, aryl, or C(O)N(R⁷)(R⁴);-   R¹ and R² are independently selected from aryl, heteroaryl, and    heterocyclyl;-   R⁴ is hydrogen, alkyl, alkenyl, acyl, aryl, heteroaryl, C(O)aryl,    C(O)alkyl, C(O)Oalkyl, C(O)Oaryl, C(O)Oheteroaryl,    C(O)N(R^(5a)R^(5b)), aralkyl, alkylsulfonyl, or

-   R^(5a) and R^(5b) are independently selected from H, alkyl, aralkyl,    and aryl;-   R⁶ is H, alkyl, or aryl; and-   R³ and R⁷ are each independently H or alkyl.

In certain embodiments, the present disclosure provides compounds ofFormula I, Formula II, and pharmaceutically acceptable salts thereof:

wherein,

-   X is C═O, NR³, C═NR³, S, S═O, S(═O)₂, or C═S;-   R¹ and R² are independently selected from aryl, heteroaryl, and    heterocyclyl;-   R⁴ is alkyl, alkenyl, acyl, C(O)aryl, C(O)alkyl, C(O)Oalkyl,    C(O)Oaryl, C(O)Oheteroaryl, C(O)N(R^(5a)R^(5b)), aralkyl,    alkylsulfonyl, or

-   R^(5a) and R^(5b) are independently selected from H, alkyl, aralkyl,    and aryl;-   R⁶ is H, alkyl, or aryl; and-   R³ and R⁷ are each independently H or alkyl.

In certain aspects, the present disclosure provides methods ofinhibiting β-catenin, comprising of administering to a subject aneffective amount of a compound of Formula I, Formula II, or Formula III.

In certain aspects, the present disclosure provides methods of treatingcancer comprising of administering to a subject in need of a treatmentfor cancer an effective amount of a compound of Formula I, Formula II,or Formula III. In some embodiments, the cancer is colorectal cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. The Wnt-β-catenin signaling pathway plays a critical role indevelopment, stem cell self-renewal, and oncogenesis. The level ofWnt/β-catenin signaling is dependent on the stability and cellularlocation of β-catenin.

FIG. 2. The hyper activated Wnt/β-catenin signaling pathway has beenfound to be associated with various types of human cancers, most notablycolorectal cancers (CRCs) due to APC and CTNNB1 (β-catenin) mutations.

FIG. 3. Left: In the absence of a Wnt signal, β-catenin is degraded by acomplex of proteins including Axin, APC, the Ser/Thr kinases GSK-3 andCK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase β-TrCP.The complex interacts with a β-TrCP recognition site on β-catenin byphosphorylation of a conserved Ser/Thr rich sequence near the aminoterminus. Phosphorylation requires scaffolding of GSK-3 and CK1 andβ-catenin by Axin. After phosphorylation and ubiquitination, β-cateninis degraded by the proteasome. Dvl is also required for activating thepathway. In the nucleus, TCF is in an inactive state as a result ofbinding to the repressor Groucho. Center: Binding of Wnt to itsreceptors induces the association of Axin with phosphorylatedlipoprotein receptor-related protein (LRP). The destruction complexdecomposes, and β-catenin is stabilized. β-catenin subsequently binds toTCF in the nucleus and upregulates target genes. Right: Mutations in APCdisrupt the degradation complex, thereby leading to the activation ofthe Wnt-β-catenin signaling pathway.

FIG. 4. In the absence of Wnt signaling, TCF interacts with corepressorsTLE1 and HDAC1, found on the chromatin, which repress Wnt target genes.On Wnt stimulation, stabilized β-catenin is translocated to the nucleusand interacts with TBL1/TBLR1. TBL1/TBLR1 and β-catenin mutuallyfacilitate their binding to the Wnt target-gene promoter, and as aresult displace the corepressors TLE and HDAC1. In addition to relievingTCF repression, β-catenin activates Wnt target gene expression byrecruiting transcriptional coactivators, such as BCL9/PYGO and CBP.

FIG. 5A. Screening of JC inhibitors for Wnt/β-catenin-mediatedtranscription. 293T/Top cells were treated with 20 mM of LiCl andincreasing concentration of JC001 as indicated. JC001 was shown toinhibit Topflash reporter activities induced by LiCl in 293 T/Top cells.

FIG. 5B. Analysis of luciferase activity of 293T/Top cells treated withthe indicated JC inhibitors relative to control (con). 293T/Top cellswere treated with 20 mM of LiCl and 250 nM of Wnt inhibitors asindicated. Luciferase activities were measured 15 hours post treatment.Values are mean±s.d. for triplicate samples from a representativeexperiment. Several compounds were found to possess inhibitory activity.

FIG. 6A. Screening of JC inhibitors for Wnt/β-catenin-mediatedtranscription. Analysis of luciferase activity of 293T/Top/β-cat* cellstreated with the indicated inhibitors (JC039-JC067) relative to control(con). Several compounds were found to possess inhibitory activity.

FIG. 6B. Screening of JC inhibitors for Wnt/β-catenin-mediatedtranscription. Analysis of luciferase activity of 293T/Top/β-cat* cellstreated with the indicated inhibitors (JC068-JC099) relative to control(con). Several compounds were found to possess inhibitory activity.

FIG. 6C. Inhibitory activities of JC001, JC026, JC049, JC094, JC098,JC099 and JC106 measured with Topflash reporter. 293T/Top/β-cat* cellswere treated with 250 nM of inhibitors as indicated. Luciferaseactivities were measured 15 hours post treatment. Values are mean±s.d.for triplicate samples from a representative experiment. Severalcompounds were found to possess inhibitory activity.

FIG. 7A. JC Wnt inhibitors suppress CRC cells growth in vivo. The growthof SW480 tumor xenografts are inhibited by JC inhibitors as indicated.Animals were treated with 10 mg/kg of the indicated drug on day 12 to22. JC026, JC049, JC060, and JC070 significantly reduced tumor volumes.

FIG. 7B. Comparisons of tumor sizes at the end of treatment. Treatmentwith JC026, JC049, JC060, and JC070 significantly reduced the size oftumors recovered.

FIG. 7C. Comparisons of tumor weights at the end of treatment. Tumorsfrom nude mice were dissected and weighed. *P<0.05; **P<0.01, unpaired2-tailed Student's t-Test. Treatment with JC026, JC049, JC060, and JC070significantly reduced the weight of tumors recovered.

FIG. 7D. Treatment with JC Wnt inhibitors has no effect on nude micebody weight.

FIG. 8A. Treatment with JC Wnt inhibitors suppress CRC cells growth invivo. The growth of SW480 tumor xenografts are inhibited by JCinhibitors as indicated Animals were treated with 10 mg/kg of theindicated drug on day 12 to day 20. Treatment with JC001, JC049, andJC099 significantly reduced tumor volumes.

FIG. 8B. Comparisons of actual tumor sizes at the end of treatment.Treatment with JC001, JC049, JC098, and JC099 reduced the size of tumorsrecovered.

FIG. 8C. Comparisons of actual tumor weights at the end of treatment.Tumors from nude mice were dissected and weighed. *P<0.05; **P<0.01,unpaired 2-tailed Student's t-Test. Treatment with JC001, JC049, andJC099 significantly reduced the weight of tumors recovered.

FIG. 9A. Treatment with JC Wnt inhibitors suppress CRC cells growth invivo. The growth of SW480 tumor xenografts are inhibited by JCinhibitors as indicated. Animals were treated with 10 mg/kg of theindicated drug treatment on day 12 to day 21. Treatment with JC049,JC060, JC081, JC082, and JC094 was found to significantly reduce tumorvolume.

FIG. 9B. Comparisons of tumor sizes at the end of treatment. Tumors fromnude mice were dissected and weighed. Treatment with JC049, JC060,JC081, JC082, and JC094 were found to significantly reduced the size ofthe tumors recovered.

FIG. 9C. Comparisons of tumor weights at the end of treatment. Tumorsfrom nude mice were dissected and weighed. *P<0.05; **P<0.01, unpaired2-tailed Student's t-Test. Treatment with JC049, JC060, JC081, JC082,and JC094 was found to significantly reduce the weight of tumorsrecovered.

FIG. 10. Treatment with JC Wnt inhibitors suppress the tumor sphereformation of colorectal cancer stem cells. ALDH⁺HCT116 cells weretreated with JC Wnt inhibitors as indicated. Tumor spheres were observedunder a microscope 2 weeks later. All of the tested compounds showed areduction in tumor sphere formation.

FIG. 11. JC Wnt inhibitors suppress the tumor sphere formation of HNSCCcancer stem cells. ALDH⁺CD44^(high)SCC1 cells were treated with JC Wntinhibitors as indicated. Tumor spheres were observed under a microscope2 weeks later. All of the tested compounds showed a reduction in tumorsphere formation.

FIG. 12. JC Wnt inhibitors suppress the tumorsphere formation of livercancer stem cells. CD13highCD133highHep3B cells were treated with JC Wntinhibitors as indicated. Tumorspheres were observed under the microscope2 weeks later. All of the tested compounds showed a reduction in tumorsphere formation.

FIG. 13. JC Wnt inhibitors suppress the tumorsphere formation of HNSCCcancer stem cells. ALDH⁺MDA-MB-231 cells were treated with JC Wntinhibitors as indicated. Tumorspheres were observed under the microscope2 weeks later. All of the tested compounds showed a reduction in tumorsphere formation.

FIG. 14A. depicts the screening of JC inhibitors forWnt/β-catenin-mediated transcription. Analysis of luciferase activity of293T/Top/β-cat* cells treated with the indicated inhibitors(JC100-JC109) relative to control (con). Several compounds were found topossess inhibitory activity. JC049 as a positive control.

FIG. 14B. depicts the screening of JC inhibitors forWnt/β-catenin-mediated transcription. Analysis of luciferase activity of293T/Top/β-cat* cells treated with the indicated inhibitors(JC110-JC118) relative to control (con). Several compounds were found topossess inhibitory activity.

FIG. 14C. depicts the screening of JC inhibitors forWnt/β-catenin-mediated transcription. Analysis of luciferase activity of293T/Top/β-cat* cells treated with the indicated inhibitors(JC119-JC130) relative to control (con). Several compounds were found topossess inhibitory activity.

FIG. 15A. depicts the screening of JC inhibitors forWnt/β-catenin-mediated transcription. Analysis of luciferase activity of293T/Top/β-cat* cells treated with the indicated inhibitors(JC131-JC135) relative to control (con). Several compounds were found topossess inhibitory activity.

FIG. 15B. depicts the screening of JC inhibitors forWnt/β-catenin-mediated transcription. Analysis of luciferase activity of293T/Top/β-cat* cells treated with the indicated inhibitors(JC136-JC139) relative to control (con). Several compounds were found topossess inhibitory activity.

FIG. 15C. depicts the screening of JC inhibitors forWnt/β-catenin-mediated transcription. Analysis of luciferase activity of293T/Top/β-cat* cells treated with the indicated inhibitors(JC140-JC144) relative to control (con). Several compounds were found topossess inhibitory activity.

FIG. 16A. depicts the comparisons of actual tumor sizes at the end oftreatment. Treatment with JC049, JC137, and JC138 reduced the size oftumors recovered.

FIG. 16B. depicts the comparisons of tumor weights at the end oftreatment. Tumors from nude mice were dissected and weighed. *P<0.05;unpaired 2-tailed Student's t-Test. Treatment with JC049 and JC138significantly reduced the weight of tumors recovered.

FIG. 16C. depicts JC Wnt inhibitors suppress CRC cells growth in vivo.The growth of SW480 tumor xenografts are inhibited by JC inhibitors asindicated. Animals were treated with 10 mg/kg of the indicated drug onday 12 to 22. JC049 and JC138 significantly reduced tumor volumes.

FIG. 16D. depicts that treatment with JC Wnt inhibitors has no effect onnude mice body weight.

DETAILED DESCRIPTION OF THE INVENTION

The Wnt-β-catenin signaling pathway plays a critical role indevelopment, stem cell self-renewal, and oncogenesis. The level ofWnt/β-catenin signaling is determined by the stability and cellularlocation of β-catenin. In the absence of Wnt stimulation, there is asmall pool of cytosolic β-catenin due to constitutive phosphorylation bya complex containing AXIN, APC and GSK3. Phospho-β-catenin is then bythe ubiquitin/proteasome degradation pathway. Upon Wnt stimulation, theAXIN/APC/GSK3 complex is antagonized, causing the accumulation ofphosphorylated β-catenin, which translocates into the nucleus. There itcomplexes with transcription factors, most notably members of the TCFfamily of DNA-binding proteins. Without β-catenin, TCFs are thought tofunction as repressors of Wnt target gene expression, in part byinteracting with transcriptional co-repressors of the Groucho/TLE familyproteins, which recruit HDACs to maintain the gene silencing. β-catenindirectly displaces TLE from TCF through competitive binding. In additionto relieving TCF repression, β-catenin may activate Wnt target geneexpression by recruiting additional proteins to TCF-bound chromatin. TheN-terminal portion of β-catenin binds to BCL9 and BCL9 acts as anadaptor between β-catenin and PYGO2 which promotes transcriptionalactivation. Several transcription complexes or coactivators, includingTBL1/TBLR1, the histone acetyl transferase CBP/p300,polymerase-associated factor 1 (PAF1) and the chromatin remodeler BRG1have been identified to be recruited by the central of C-terminus partof β-catenin. These interactions contribute to the ability ofTCF/β-catenin to activate Wnt target genes, supporting the model thatβ-catenin converts TCFs from repressors into transcriptional activators.

Abnormal activation of Wnt/β-catenin signaling has been demonstrated toplay an important role in the development of colorectal cancer (Dow, L.E. et al. Cell 161, 1539-1552, 2015; Clevers, H. & Nusse, R. Cell 149,1192-1205, 2012; Nusse, R. & Clevers, H. Cell 169, 985-999, 2017). Thetransition of an intestinal epithelial cell into a fully transformedmetastatic colorectal cancer cell follows a series of inactivating andactivating mutations of various tumor suppressors and oncogenes (Fearon,E. R. Annu Rev Pathol 6, 479-507, 2011). The initiating event ofintestinal carcinogenesis is commonly caused by mutations in the keycomponents of the Wnt signaling pathway (e.g., APC or CTNNB1), whichlead to stabilization of β-catenin and subsequent constitutivetranscription by the β-catenin/TCF complex. This triggers expansion andtransformation of the stem cell compartment and leads subsequently tothe development of adenomatous polyps (van de Wetering, M. et al. Cell111, 241-250, 2002). During the course of tumorigenesis, additionalmutations in other oncogenes and tumor suppressors, such as KRAS andTP53, are usually acquired. Tumors continue to progress once carcinomashave formed and accumulated loss of tumor suppressor genes correlateswith the ability of the carcinomas to metastasize and cause death.However, no approved drugs are available in the clinic for treatment viatargeting of the Wnt signaling pathway, despite substantial effortinvested into therapeutic development of Wnt inhibitors in the past twodecades (Novellasdemunt, L., Antas, P. & Li, V. S. Am J Physiol CellPhysiol 309, C511-521, 2015; Nusse, R. & Clevers, H. Cell 169, 985-999,2017).

In certain aspects, the present disclosure provides compound of FormulaI, Formula II, or a pharmaceutically acceptable salt thereof:

wherein,

-   X is C═O, NR³, C═NR³, S, S═O, S(═O)₂, or C═S;-   Y is heteroaryl, aryl, or C(O)N(R⁷)(R⁴);-   R¹ and R² are independently selected from aryl, heteroaryl, and    heterocyclyl;-   R⁴ is hydrogen, alkyl, alkenyl, acyl, aryl, heteroaryl, C(O)aryl,    C(O)alkyl, C(O)Oalkyl, C(O)Oaryl, C(O)Oheteroaryl,    C(O)N(R^(5a)R^(5b)), aralkyl, alkylsulfonyl, or

-   R⁵ and R^(5b) are independently selected from H, alkyl, aralkyl, and    aryl;-   R⁶ is H, alkyl, or aryl; and-   R³ and R⁷ are each independently H or alkyl.

In other embodiments, R⁴ is hydrogen. In yet other embodiments, R⁴ isnot hydrogen. In other embodiments, R⁴ is alkyl, alkenyl, acyl, aryl,heteroaryl, C(O)aryl, C(O)alkyl, C(O)Oalkyl, C(O)Oaryl, C(O)Oheteroaryl,C(O)N(R^(5a)R^(5b)), aralkyl, alkylsulfonyl, or

In certain embodiments of Formula I, Formula II, or Formula III, R¹ isaryl or heteroaryl. In certain embodiments, R¹ is aryl, such as phenylor naphthyl, preferably fluorophenyl or difluorophenyl, most preferably3-fluorophenyl or 3,4-difluorophenyl. In other embodiments, R¹ isheteroaryl, such as pyridyl, furanyl, thiophenyl, indolyl, orbenzofuranyl. In certain embodiments, R¹ is further substituted with atleast one substituent selected from alkyl, alkoxy, halo (e.g., fluoro,chloro, or bromo, preferably fluoro), aralkyl, and C(O)Oalkyl. Incertain preferred embodiments, R¹ is further substituted with halo(e.g., fluoro, chloro, or bromo, preferably fluoro) or alkyl (e.g.,trifluoromethyl).

In certain embodiments of Formula I, Formula II, or Formula III, R² isaryl or heteroaryl. In certain embodiments, R² is aryl, such as phenylor naphthyl, preferably fluorophenyl or difluorophenyl, most preferably3-fluorophenyl or 3,4-difluorophenyl. In other embodiments, R² isheteroaryl, such as pyridyl, furanyl, thiophenyl, indolyl, orbenzofuranyl. In certain embodiments, R² is further substituted with atleast one substituent selected from alkyl, alkoxy, halo (e.g., fluoro,chloro, or bromo, preferably fluoro), aralkyl, and C(O)Oalkyl. Incertain preferred embodiments, R² is further substituted with halo(e.g., fluoro, chloro, or bromo, preferably fluoro) or alkyl (e.g.,trifluoromethyl).

In certain embodiments of Formula I, Formula II, or Formula III, R¹ andR² are different. In other preferred embodiments, R¹ and R² are thesame.

In certain embodiments, the compound is represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein,

-   X is C═O, NR³, C═NR³, S, S═O, S(═O)₂, or C═S;-   R¹ and R² are independently selected from aryl, heteroaryl, and    heterocyclyl;-   R⁴ is alkyl, alkenyl, acyl, C(O)aryl, C(O)alkyl, C(O)Oalkyl,    C(O)Oaryl, C(O)Oheteroaryl, C(O)N(R^(5a)R^(5b)), aralkyl,    alkylsulfonyl, or

-   R⁵ and R^(5b) are independently selected from H, alkyl, aralkyl, and    aryl;-   R⁶ is H, alkyl, or aryl; and-   R³ and R⁷ are each independently H or alkyl.

In certain embodiments, the compound is represented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein,

-   X is C═O, NR³, C═NR³, S, S═O, S(═O)₂, or C═S;-   R¹ and R² are independently selected from aryl, heteroaryl, and    heterocyclyl;

In certain embodiments, X is S(═O)₂.

In certain embodiments of Formula I or Formula II, the compound isrepresented by Formula Ia or Formula IIa:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula I, the compound is represented byFormula Ib

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula I, the compound is represented byFormula Ic or Id:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula II, the compound is represented byFormula IIb:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula II, the compound is represented byFormula IIc or IId:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula I or Formula II, R⁴ isC(O)N(R^(5a)R^(5b)) or

In certain embodiments, R⁴ is

In certain embodiments, R^(5a) and R^(5b) are both alkyl, such asmethyl. In certain embodiments, R⁶ is aryl, such as phenyl. In otherpreferred embodiments, R⁴ is C(O)N(R^(5a)R^(5b)).

In certain embodiments of Formula I or Formula II, R^(5a) is alkyl, suchas methyl or ethyl. In certain embodiments, R^(5a) is furthersubstituted with hydroxyl or amino, such as dimethylamino. In certainembodiments, R^(5a) is aryl, such as phenyl.

In certain embodiments of Formula I or Formula II, in certain preferredembodiments, R^(5b) is H. In other embodiments, R^(5b) is aralkyl, suchas benzyl. In yet other embodiments, R^(5b) is alkyl, such a methyl.

In certain embodiments of Formula I or Formula II, R⁴ is alkyl, alkenyl,acyl, C(O)alkyl, C(O)Oalkyl, aralkyl, or alkylsulfonyl. In certainpreferred embodiments, R⁴ is further substituted with at least one basicamino substituent. In certain embodiments, the basic amino substituentis NH₂. In other embodiments, the basic amino substituent is alkylamino,preferably dialkylamino, such as dimethylamino, diethylamino, ordi(methoxyethyl)amino. In certain preferred embodiments the basicaminosubstituent is di(methoxyethyl)amino. In other embodiments, thebasic amino substituent is a basic nitrogen containing heterocycle, suchas azepanyl, pyrrolidinyl (e.g., pyrrolidine or N-methyl pyrrolidine),piperidyl, morpholinyl, piperazinyl (e.g., N-methylpiperazine or1-(4-fluorophenyl)piperazine), piperidonyl, or thiomorpholinyl.

In certain embodiments of Formula I or Formula II, R⁴ is furthersubstituted with at least one substituent selected from C(O)Oalkyl (suchas C(O)Omethyl, or C(O)Oethyl), C(O)alkyl (such as acetyl), alkenyl(such as dimethyl fumaratyl or aminoallyl (e.g., dimethylaminoallyl)),thio (such as phenylthio), alkenyl (such as vinyl), carboxyl, amido(such as C(O)pyrrolidinyl), and alkyloxy (such as methoxy).

In yet other embodiments of Formula I or Formula II, R⁴ is C(O)alkyl. Incertain embodiments, the alkyl is further substituted withcarbamodithioate (e.g., morpholine carbodithioate).

In yet other preferred embodiments of Formula I or Formula II, R⁴ isC(O)aryl or C(O)Oaryl. In certain embodiments, the aryl of R⁴ is furthersubstituted, preferably at a para position, with at least one basicamino substituent. In certain embodiments, the basic amino substituentis amino, preferably dialkylamino, such as dimethylamino. In otherembodiments, the basic amino substituent is aminoalkyloxy (such asdimethylaminoethyloxy, diethylaminoethyloxy, or2-(piperidin-1-yl)ethanoxy), aminoalkylthio (such asdimethylaminoethylthio), or aminoalkylamino (such asdimethylaminoethylamino). In certain preferred embodiments, the basicamino substitutent is dimethylaminoethyloxy or diethylaminoethyloxy. Inother embodiments, the basic amino substituent is aminoalkyloxy (e.g.,morpholinylalkyloxy).

In certain embodiments of Formula I or Formula II, the aryl of R⁴ isfurther substituted, preferably at a para-position, with at least onesubstituent selected from alkyl, such as trifluoromethyl, and halo, suchas fluoro or chloro. In other embodiments, the aryl of R⁴ is furthersubstituted, preferably at a para-position, with at least onesubstituent selected from alkynyloxy (e.g., ethynyloxy).

In certain preferred embodiments of Formula I or Formula II, the aryl ofR⁴ is further substituted, preferably at a meta- or ortho-position, withat least one substituent selected from alkyl, such as trifluoromethyl,and halo, such as fluoro or chloro.

In other embodiments of Formula I or Formula II, R⁴ is alkylsulfonyl,and is preferably further substituted with amino, preferablydialkylamino, such as dimethylamino or diethylamino, or alkyoxy, such asmethoxy.

In certain embodiments of Formula I or Formula II, the compound isrepresented by Formula IIe:

wherein

-   R⁷ is H or alkyl; and-   R⁸ is aminoalkyl or aryl.

In certain embodiments, the compound of Formula IIe is apharmaceutically acceptable salt of the compound of Formula IIe.

In other embodiments, R⁸ is aryl, such as phenyl, further substituted(preferably at a para-position) with aminoalkyl, such asdimethylaminoethyl, or aminoalkoxy, such as 2-(piperidin-1-yl)ethyloxy.

In certain embodiments, the compound is represented by Formula III:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula III, the compound is represented byFormula Ma:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula III, Y is aryl. In certain the aryl issubstituted with at least one basic amino substituent. In certainembodiments, the basic amino substituent is NH₂. In certain embodiments,the basic amino substituent is alkylamino, preferably dialkylamino, suchas dimethylamino, diethylamino, or di(methoxyethyl)amino. In certainembodiments, the basic amino substituent is aminoalkyloxy (such asdimethylaminoethyloxy, diethylaminoethyloxy, or2-(piperidin-1-yl)ethanoxy), aminoalkylthio (such asdimethylaminoethylthio), or aminoalkylamino (such asdimethylaminoethylamino). In certain preferred embodiments, the basicamino substituent is aminoalkyloxy (such as dimethylaminoethyloxy,diethylaminoethyloxy or 2-(piperidin-1-yl)ethanoxy). In even morepreferred embodiments, the basic amino substituent isdimethylaminoethyloxy. In other embodiments, the basic amino substituentis a basic nitrogen containing heterocycle, such as azepanyl,pyrrolidinyl (e.g., pyrrolidine or N-methyl pyrrolidine), piperidyl,morpholinyl, piperazinyl (e.g., N-methylpiperazine or1-(4-fluorophenyl)piperazine), piperidonyl, or thiomorpholinyl. In yetother embodiments, the basic amino substituent is aminoalkyloxy (e.g.,morpholinylalkyloxy). In certain embodiments, the aryl is furthersubstituted with at least one substituent selected from C(O)Oalkyl (suchas C(O)Omethyl, or C(O)Oethyl), C(O)alkyl (such as acetyl), alkenyl(such as dimethyl fumaratyl or aminoallyl (e.g., dimethylaminoallyl)),thio (such as phenylthio), alkenyl (such as vinyl), carboxyl, amido(such as C(O)pyrrolidinyl), and alkyloxy (such as methoxy).

In other embodiments of Formula III, Y is C(O)N(R⁷)(R⁴).

In certain embodiments of Formula III, R⁷ is alkyl, such as methyl. Inother preferred embodiments, R⁷ is H.

In certain preferred embodiments of Formula III, R⁴ is aryl. In certainembodiments, the aryl is further substituted, preferably at a paraposition, with at least one basic amino substituent. In certainembodiments, the basic amino substituent is amino, preferablydialkylamino, such as dimethylamino. In certain embodiments, the basicamino substituent is aminoalkyl, preferably dialkylaminoalkyl, such asdimethylaminomethyl or dimethylaminoethyl. In certain embodiments, thebasic amino substituent is aminoalkyloxy (such as dimethylaminoethyloxy,diethylaminoethyloxy, or 2-(piperidin-1-yl)ethanoxy), aminoalkylthio(such as dimethylaminoethylthio), or aminoalkylamino (such asdimethylaminoethylamino). In certain preferred embodiments, the basicamino substituent is aminoalkyloxy (such as dimethylaminoethyloxy,diethylaminoethyloxy or 2-(piperidin-1-yl)ethanoxy). In even morepreferred embodiments, the basic amino substituent isdimethylaminoethyloxy. In other embodiments, the basic amino substituentis aminoalkyloxy (e.g., morpholinylalkyloxy). In certain embodiments,the aryl is further substituted, preferably at a para-position, with atleast one substituent selected from alkyl, such as trifluoromethyl, andhalo, such as fluoro or chloro. In other embodiments, the aryl isfurther substituted, preferably at a para-position, with at least onesubstituent selected from alkynloxy (e.g., ethynyloxy). In yet otherembodiments, the aryl is further substituted, preferably at a meta- orortho-position, with at least one substituent selected from alkyl, suchas trifluoromethyl, and halo, such as fluoro or chloro.

In certain embodiments of Formula I or Formula II, R⁷ is alkyl, such asmethyl. In other preferred embodiments, R⁷ is H. In certain preferredembodiments of Formula lie, R⁸ is aminoalkyl, preferablydialkylaminoalkyl, such as dimethylaminoethyl.

In certain aspects, the compound is selected from a compound of Table 1.

TABLE 1 Exemplary Compounds of the Present Invention

JC001

JC002

JC003

JC004

JC005

JC006

JC007

JC008

JC009

JC010

JC011

JC012

JC013

JC014

JC015

JC016

JC017

JC018

JC019

JC020

JC021

JC022

JC023

JC024

JC025

JC026

JC027

JC028

JC029

JC030

JC031

JC032

JC033

JC034

JC035

JC036

JC037

JC038

JC039

JC040

JC041

JC043

JC044

JC045

JC046

JC047

JC048

JC049

JC050

JC051

JC052

JC053

JC054

JC055

JC056

JC057

JC058

JC059

JC060

JC061

JC062

JC063

JC064

JC065

JC066

JC067

JC068

JC069

JC070

JC071

JC072

JC073

JC074

JC075

JC076

JC077

JC078

JC080

JC081

JC082

JC083

JC084

JC085

JC086

JC087

JC088

JC089

JC090

JC091

JC092

JC093

JC094

JC095

JC096

JC097

JC098

JC099

JC100

JC101

JC102

JC103

JC104

JC105

JC106

JC107

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In certain aspects, the present disclosure provides pharmaceuticalcompositions comprising a compound of Formula I, II, or III, and apharmaceutically acceptable excipient.

In certain embodiments, the present disclosure provides a method ofinhibiting β-catenin or a variant thereof, comprising administering to asubject a compound or composition of Formula I, II, or III. In certainembodiments, the β-catenin is wild type. In certain embodiments, theβ-catenin is mutated. In certain embodiments, the β-catenin isβ-catenin*. In certain embodiments, the β-catenin is mutated at Ser33,Ser37, Thr41 and Ser45. In certain embodiments, the β-catenin is mutatedat Ser33, Ser37, Thr41 or Ser45.

In certain aspects, the present disclosure provides methods of treatingcancer comprising of administering to a subject in need of a treatmentfor cancer an effective amount of a compound of Formula I, Formula II,Formula III, or of a compound described herein. In certain embodiments,the cancer is bladder cancer, bone cancer, brain cancer, breast cancer,cardiac cancer, cervical cancer, colon cancer, colorectal cancer,esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinalcancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer,leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreaticcancer, penile cancer, testicular germ cell cancer, thymoma and thymiccarcinoma, lung cancer, ovarian cancer, and prostate cancer. In certainembodiments, the cancer is colorectal cancer.

Definitions

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature used inconnection with, and techniques of, chemistry, cell and tissue culture,molecular biology, cell and cancer biology, neurobiology,neurochemistry, virology, immunology, microbiology, pharmacology,genetics and protein and nucleic acid chemistry, described herein, arethose well known and commonly used in the art.

The methods and techniques of the present disclosure are generallyperformed, unless otherwise indicated, according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout thisspecification. See, e.g. “Principles of Neural Science”, McGraw-HillMedical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”,Oxford University Press, Inc. (1995); Lodish et al., “Molecular CellBiology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths etal., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co.,N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”,Sinauer Associates, Inc., Sunderland, Mass. (2000).

Chemistry terms used herein, unless otherwise defined herein, are usedaccording to conventional usage in the art, as exemplified by “TheMcGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill,San Francisco, Calif. (1985).

All of the above, and any other publications, patents and publishedpatent applications referred to in this application are specificallyincorporated by reference herein. In case of conflict, the presentspecification, including its specific definitions, will control.

The term “agent” is used herein to denote a chemical compound (such asan organic or inorganic compound, a mixture of chemical compounds), abiological macromolecule (such as a nucleic acid, an antibody, includingparts thereof as well as humanized, chimeric and human antibodies andmonoclonal antibodies, a protein or portion thereof, e.g., a peptide, alipid, a carbohydrate), or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Agents include, for example, agents whose structure isknown, and those whose structure is not known. The ability of suchagents to inhibit AR or promote AR degradation may render them suitableas “therapeutic agents” in the methods and compositions of thisdisclosure.

A “patient,” “subject,” or “individual” are used interchangeably andrefer to either a human or a non-human animal. These terms includemammals, such as humans, primates, livestock animals (including bovines,porcines, etc.), companion animals (e.g., canines, felines, etc.) androdents (e.g., mice and rats).

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. As usedherein, and as well understood in the art, “treatment” is an approachfor obtaining beneficial or desired results, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of extent of disease, stabilized (i.e. not worsening) stateof disease, preventing spread of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment.

The term “preventing” is art-recognized, and when used in relation to acondition, such as a local recurrence (e.g., pain), a disease such ascancer, a syndrome complex such as heart failure or any other medicalcondition, is well understood in the art, and includes administration ofa composition which reduces the frequency of, or delays the onset of,symptoms of a medical condition in a subject relative to a subject whichdoes not receive the composition. Thus, prevention of cancer includes,for example, reducing the number of detectable cancerous growths in apopulation of patients receiving a prophylactic treatment relative to anuntreated control population, and/or delaying the appearance ofdetectable cancerous growths in a treated population versus an untreatedcontrol population, e.g., by a statistically and/or clinicallysignificant amount.

“Administering” or “administration of” a substance, a compound or anagent to a subject can be carried out using one of a variety of methodsknown to those skilled in the art. For example, a compound or an agentcan be administered, intravenously, arterially, intradermally,intramuscularly, intraperitoneally, subcutaneously, ocularly,sublingually, orally (by ingestion), intranasally (by inhalation),intraspinally, intracerebrally, and transdermally (by absorption, e.g.,through a skin duct). A compound or agent can also appropriately beintroduced by rechargeable or biodegradable polymeric devices or otherdevices, e.g., patches and pumps, or formulations, which provide for theextended, slow or controlled release of the compound or agent.Administering can also be performed, for example, once, a plurality oftimes, and/or over one or more extended periods.

Appropriate methods of administering a substance, a compound or an agentto a subject will also depend, for example, on the age and/or thephysical condition of the subject and the chemical and biologicalproperties of the compound or agent (e.g., solubility, digestibility,bioavailability, stability and toxicity). In some embodiments, acompound or an agent is administered orally, e.g., to a subject byingestion. In some embodiments, the orally administered compound oragent is in an extended release or slow release formulation, oradministered using a device for such slow or extended release.

As used herein, the phrase “conjoint administration” refers to any formof administration of two or more different therapeutic agents such thatthe second agent is administered while the previously administeredtherapeutic agent is still effective in the body (e.g., the two agentsare simultaneously effective in the patient, which may includesynergistic effects of the two agents). For example, the differenttherapeutic compounds can be administered either in the same formulationor in separate formulations, either concomitantly or sequentially. Thus,an individual who receives such treatment can benefit from a combinedeffect of different therapeutic agents.

A “therapeutically effective amount” or a “therapeutically effectivedose” of a drug or agent is an amount of a drug or an agent that, whenadministered to a subject will have the intended therapeutic effect. Thefull therapeutic effect does not necessarily occur by administration ofone dose, and may occur only after administration of a series of doses.Thus, a therapeutically effective amount may be administered in one ormore administrations. The precise effective amount needed for a subjectwill depend upon, for example, the subject's size, health and age, andthe nature and extent of the condition being treated, such as cancer orMDS.

The skilled worker can readily determine the effective amount for agiven situation by routine experimentation.

As used herein, the terms “optional” or “optionally” mean that thesubsequently described event or circumstance may occur or may not occur,and that the description includes instances where the event orcircumstance occurs as well as instances in which it does not. Forexample, “optionally substituted alkyl” refers to the alkyl may besubstituted as well as where the alkyl is not substituted.

It is understood that substituents and substitution patterns on thecompounds of the present invention can be selected by one of ordinaryskilled person in the art to result chemically stable compounds whichcan be readily synthesized by techniques known in the art, as well asthose methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.

As used herein, the term “substituted” refers to the replacement of oneto six hydrogen radicals in a given structure with the radical of aspecified substituent including, but not limited to: hydroxyl,hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl,cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl,haloalkoxy, —OCO—CH₂—O-alkyl, —OP(O)(O-alkyl)₂ or —CH₂—OP(O)(O-alkyl)₂.Preferably, “substituted” refers to the replacement of one to fourhydrogen radicals in a given structure with the substituents mentionedabove. More preferably, one to three hydrogen radicals are replaced bythe substituents as mentioned above. It is understood that thesubstituent can be further substituted.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group having an oxygen attachedthereto. Representative alkoxy groups include methoxy, ethoxy, propoxy,tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkyl” refers to saturated aliphatic groups, includingstraight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl-substituted cycloalkyl groups, andcycloalkyl-substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁₋₃₀ for straight chains, C₃₋₃₀ for branchedchains), and more preferably 20 or fewer.

Moreover, the term “alkyl” as used throughout the specification,examples, and claims is intended to include both unsubstituted andsubstituted alkyl groups, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone, including haloalkyl groups such as trifluoromethyland 2,2,2-trifluoroethyl, etc.

The term “C_(x-y)” or “C_(x)-C_(y)”, when used in conjunction with achemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, oralkoxy is meant to include groups that contain from x to y carbons inthe chain. C₀alkyl indicates a hydrogen where the group is in a terminalposition, a bond if internal. A C₁₋₆alkyl group, for example, containsfrom one to six carbon atoms in the chain.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “amide”, as used herein, refers to a group

wherein R⁹ and R¹⁰ each independently represent a hydrogen orhydrocarbyl group, or R⁹ and R¹⁰ taken together with the N atom to whichthey are attached complete a heterocycle having from 4 to 8 atoms in thering structure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein R⁹, R¹⁰, and R¹⁰′ each independently represent a hydrogen or ahydrocarbyl group, or R⁹ and R¹⁰ taken together with the N atom to whichthey are attached complete a heterocycle having from 4 to 8 atoms in thering structure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “carbamate” is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbylgroup.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The terms “carbocycle”, “carbocyclyl”, and “carbocyclic”, as usedherein, refers to a non-aromatic saturated or unsaturated ring in whicheach atom of the ring is carbon. Preferably a carbocycle ring containsfrom 3 to 10 atoms, more preferably from 5 to 7 atoms.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR⁹ wherein R⁹represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle.

Ethers include “alkoxyalkyl” groups, which may be represented by thegeneral formula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are consideredto be hydrocarbyl for the purposes of this application, but substituentssuch as acetyl (which has a ═O substituent on the linking carbon) andethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbylgroups include, but are not limited to aryl, heteroaryl, carbocycle,heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer atoms in the substituent,preferably six or fewer. A “lower alkyl”, for example, refers to analkyl group that contains ten or fewer carbon atoms, preferably six orfewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl,or alkoxy substituents defined herein are respectively lower acyl, loweracyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy,whether they appear alone or in combination with other substituents,such as in the recitations hydroxyalkyl and aralkyl (in which case, forexample, the atoms within the aryl group are not counted when countingthe carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R⁹ and R¹⁰ independently represents hydrogen or hydrocarbyl.

The term “sulfoxide” is art-recognized and refers to the group —S(O)—.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR⁹ or—SC(O)R⁹

wherein R⁹ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl.

The term “modulate” as used herein includes the inhibition orsuppression of a function or activity (such as cell proliferation) aswell as the enhancement of a function or activity.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, excipients, adjuvants,polymers and other materials and/or dosage forms which are, within thescope of sound medical judgment, suitable for use in contact with thetissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable salt” or “salt” is used herein to refer toan acid addition salt or a basic addition salt which is suitable for orcompatible with the treatment of patients.

The term “pharmaceutically acceptable acid addition salt” as used hereinmeans any non-toxic organic or inorganic salt of any base compoundsrepresented by Formula I, II, or III. Illustrative inorganic acids whichform suitable salts include hydrochloric, hydrobromic, sulfuric andphosphoric acids, as well as metal salts such as sodium monohydrogenorthophosphate and potassium hydrogen sulfate. Illustrative organicacids that form suitable salts include mono-, di-, and tricarboxylicacids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric,fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic,phenylacetic, cinnamic and salicylic acids, as well as sulfonic acidssuch as p-toluene sulfonic and methanesulfonic acids. Either the mono ordi-acid salts can be formed, and such salts may exist in either ahydrated, solvated or substantially anhydrous form. In general, the acidaddition salts of compounds of Formula I, II, or III are more soluble inwater and various hydrophilic organic solvents, and generallydemonstrate higher melting points in comparison to their free baseforms. The selection of the appropriate salt will be known to oneskilled in the art. Other non-pharmaceutically acceptable salts, e.g.,oxalates, may be used, for example, in the isolation of compounds ofFormula I, II, or III for laboratory use, or for subsequent conversionto a pharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable basic addition salt” as usedherein means any non-toxic organic or inorganic base addition salt ofany acid compounds represented by Formula I, II, or III or any of theirintermediates. Illustrative inorganic bases which form suitable saltsinclude lithium, sodium, potassium, calcium, magnesium, or bariumhydroxide. Illustrative organic bases which form suitable salts includealiphatic, alicyclic, or aromatic organic amines such as methylamine,trimethylamine and picoline or ammonia. The selection of the appropriatesalt will be known to a person skilled in the art.

Many of the compounds useful in the methods and compositions of thisdisclosure have at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates allstereoisomeric forms such as enantiomeric and diastereoisomeric forms ofthe compounds, salts, prodrugs or mixtures thereof (including allpossible mixtures of stereoisomers). See, e.g., WO 01/062726.

Furthermore, certain compounds which contain alkenyl groups may exist asZ (zusammen) or E (entgegen) isomers. In each instance, the disclosureincludes both mixture and separate individual isomers.

Some of the compounds may also exist in tautomeric forms. Such forms,although not explicitly indicated in the formulae described herein, areintended to be included within the scope of the present disclosure.

“Prodrug” or “pharmaceutically acceptable prodrug” refers to a compoundthat is metabolized, for example hydrolyzed or oxidized, in the hostafter administration to form the compound of the present disclosure(e.g., compounds of Formula I, II, or III). Typical examples of prodrugsinclude compounds that have biologically labile or cleavable(protecting) groups on a functional moiety of the active compound.Prodrugs include compounds that can be oxidized, reduced, aminated,deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealkylated, acylated, deacylated, phosphorylated, ordephosphorylated to produce the active compound. Examples of prodrugsusing ester or phosphoramidate as biologically labile or cleavable(protecting) groups are disclosed in U.S. Pat. Nos. 6,875,751,7,585,851, and 7,964,580, the disclosures of which are incorporatedherein by reference. The prodrugs of this disclosure are metabolized toproduce a compound of Formula I, II, or III. The present disclosureincludes within its scope, prodrugs of the compounds described herein.Conventional procedures for the selection and preparation of suitableprodrugs are described, for example, in “Design of Prodrugs” Ed. H.Bundgaard, Elsevier, 1985.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filter, diluent, excipient, solvent or encapsulatingmaterial useful for formulating a drug for medicinal or therapeutic use.

The term “Log of solubility”, “Log S” or “log S” as used herein is usedin the art to quantify the aqueous solubility of a compound. The aqueoussolubility of a compound significantly affects its absorption anddistribution characteristics. A low solubility often goes along with apoor absorption. Log S value is a unit stripped logarithm (base 10) ofthe solubility measured in mol/liter.

Pharmaceutical Compositions

The compositions and methods of the present invention may be utilized totreat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered as a pharmaceutical compositioncomprising, for example, a compound of the invention and apharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are well known in the art and include, for example, aqueoussolutions such as water or physiologically buffered saline or othersolvents or vehicles such as glycols, glycerol, oils such as olive oil,or injectable organic esters. In preferred embodiments, when suchpharmaceutical compositions are for human administration, particularlyfor invasive routes of administration (i.e., routes, such as injectionor implantation, that circumvent transport or diffusion through anepithelial barrier), the aqueous solution is pyrogen-free, orsubstantially pyrogen-free. The excipients can be chosen, for example,to effect delayed release of an agent or to selectively target one ormore cells, tissues or organs. The pharmaceutical composition can be indosage unit form such as tablet, capsule (including sprinkle capsule andgelatin capsule), granule, lyophile for reconstitution, powder,solution, syrup, suppository, injection or the like. The composition canalso be present in a transdermal delivery system, e.g., a skin patch.The composition can also be present in a solution suitable for topicaladministration, such as a lotion, cream, or ointment.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the invention. Such physiologically acceptable agentsinclude, for example, carbohydrates, such as glucose, sucrose ordextrans, antioxidants, such as ascorbic acid or glutathione, chelatingagents, low molecular weight proteins or other stabilizers orexcipients. The choice of a pharmaceutically acceptable carrier,including a physiologically acceptable agent, depends, for example, onthe route of administration of the composition. The preparation orpharmaceutical composition can be a selfemulsifying drug delivery systemor a selfmicroemulsifying drug delivery system. The pharmaceuticalcomposition (preparation) also can be a liposome or other polymermatrix, which can have incorporated therein, for example, a compound ofthe invention. Liposomes, for example, which comprise phospholipids orother lipids, are nontoxic, physiologically acceptable and metabolizablecarriers that are relatively simple to make and administer.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules (including sprinkle capsulesand gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue); absorption through the oral mucosa (e.g.,sublingually); subcutaneously; transdermally (for example as a patchapplied to the skin); and topically (for example, as a cream, ointmentor spray applied to the skin). The compound may also be formulated forinhalation. In certain embodiments, a compound may be simply dissolvedor suspended in sterile water. Details of appropriate routes ofadministration and compositions suitable for same can be found in, forexample, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231,5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an active compound, such as a compound ofthe invention, with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules (including sprinkle capsules and gelatin capsules),cachets, pills, tablets, lozenges (using a flavored basis, usuallysucrose and acacia or tragacanth), lyophile, powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a compound of the present invention as anactive ingredient. Compositions or compounds may also be administered asa bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), the active ingredient is mixedwith one or more pharmaceutically acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; (10) complexing agents,such as, modified and unmodified cyclodextrins; and (11) coloringagents. In the case of capsules (including sprinkle capsules and gelatincapsules), tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the active compound in theproper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.Pharmaceutical compositions suitable for parenteral administrationcomprise one or more active compounds in combination with one or morepharmaceutically acceptable sterile isotonic aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be givenper se or as a pharmaceutical composition containing, for example, 0.1to 99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinaceous biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound(s) being employed, the duration of the treatment,other drugs, compounds and/or materials used in combination with theparticular compound(s) employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. By “therapeutically effective amount” ismeant the concentration of a compound that is sufficient to elicit thedesired therapeutic effect. It is generally understood that theeffective amount of the compound will vary according to the weight, sex,age, and medical history of the subject. Other factors which influencethe effective amount may include, but are not limited to, the severityof the patient's condition, the disorder being treated, the stability ofthe compound, and, if desired, another type of therapeutic agent beingadministered with the compound of the invention. A larger total dose canbe delivered by multiple administrations of the agent. Methods todetermine efficacy and dosage are known to those skilled in the art(Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the invention will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentinvention, the active compound may be administered two or three timesdaily. In preferred embodiments, the active compound will beadministered once daily.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans; and other mammals such as equines,cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

In certain embodiments, compounds of the invention may be used alone orconjointly administered with another type of therapeutic agent.

The present disclosure includes the use of pharmaceutically acceptablesalts of compounds of the invention in the compositions and methods ofthe present invention. In certain embodiments, contemplated salts of theinvention include, but are not limited to, alkyl, dialkyl, trialkyl ortetra-alkyl ammonium salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, L-arginine,benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine,ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium,L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine,potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine,tromethamine, and zinc salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, Na, Ca, K, Mg, Zn orother metal salts. In certain embodiments, contemplated salts of theinvention include, but are not limited to, 1-hydroxy-2-naphthoic acid,2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaricacid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid,adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid,benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capricacid (decanoic acid), caproic acid (hexanoic acid), caprylic acid(octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, fumaric acid, galactaric acid, gentisic acid,d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid,glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid,hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid,lactobionic acid, lauric acid, maleic acid, 1-malic acid, malonic acid,mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid,oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionicacid, 1-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid,succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid,p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid acidsalts.

The pharmaceutically acceptable acid addition salts can also exist asvarious solvates, such as with water, methanol, ethanol,dimethylformamide, and the like. Mixtures of such solvates can also beprepared. The source of such solvate can be from the solvent ofcrystallization, inherent in the solvent of preparation orcrystallization, or adventitious to such solvent.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

EXAMPLES

The invention now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1: Preparation of Exemplary Compounds General Procedure A:

Certain compounds disclosed herein (e.g., JC001-JC006 and theiranalogues) were generally prepared by reaction of the correspondingaldehydes, e.g., benzaldehyde, with piperidin-4-one hydrogen chloride inthe present of 40% aq. sodium hydroxide to give the(3,5-diarylmethylidene)piperidone, e.g.,(3,5-dibenzylidene)piperidin-4-one. Acylation of(3,5-dibenzylidene)piperidin-4-one with acryloyl chloride under basicconditions afforded the 1-acryloyl (3,5-dibenzylidene)piperidin-4-one.Michael addition of an amine, e.g., dimethylamine, afforded the(3,5-diarylmethylidene-1-(3-dialkylamino)propanoyl)piperidin-4-one,e.g., (3,5-dibenzyl-idene-1-(3-dimethylamino)propanoyl)piperidin-4-one.

Preparation of JC001:

To a mixture of piperidin-4-one hydrogen chloride (135.59 mg, 1 mmol,1.0 equiv.) and methanol (2.0 mL) in a round bottom flask was addeddropwise 40% aqueous sodium hydroxide (1.0 mL) and the reaction mixturewas stirred for 5 min. To this mixture was added benzaldehyde (265.3 mg,2.5 mmol, 2.5 equiv.). The reaction mixture was then allowed to stir at21° C. for 3 h at which time a yellow solid had precipitated. The yellowprecipitate thus obtained was filtered, washed with water and coldmethanol and dried to get pure piperidone product (242 mg, 88% yield).

A mixture of 3,5-di((E)-benzylidene)piperidin-4-one (137.7 mg, 0.5 mmol,1.0 equiv.) and anhydrous triethylamine (105 μL, 0.75 mmol, 1.5 equiv.)in dichloromethane was maintained at 0° C. (ice bath). To this cooledmixture was added dropwise acryloyl chloride (61 μL, 0.75 mmol, 1.5equiv.). After the complete addition of the acryloyl chloride, thereaction mixture was slowly warmed up to 21° C. and stirred for afurther 4 h. After completion of the reaction, the solvent wasevaporated and the residue thus obtained was washed with water, filteredand dried. The crude amide product was pure enough to be used for thenext step.

A mixture of crude 1-acryloyl-3,5-di((E)-benzylidene)piperidin-4-one(164.7 mg, 0.5 mmol, 1.0 equiv.),2,6-bis(1,1-dimethylethyl)-4-methylphenol (1.1 mg, 0.005 mmol, 1%) anddimethylamine (2N in THF) (0.375 mL, 0.75 mmol, 1.5 equiv.) in 1.0 mLanhydrous THF was heated to 65° C. under argon for 12 h. The solvent wasevaporated and flash chromatography of the residue (gradient elution 5%methanol/EtOAc-10% methanol/EtOAc) to give a yellow solid, dried thesolvent by vacuum and added dry DCM (10 mL), filtered by cotton to getJC001 (131 mg, 70% yield) as a yellow solid.

The following compounds were synthesized by procedure A: JC001, JC002,JC003, JC004, JC005, JC006, JC012, JC013, JC014, JC015, JC016, JC017,JC018, JC019, JC020, JC021, JC022, JC023, JC024, JC025, JC027, JC028,JC029, JC030, JC031, JC032, JC033, JC034, JC035, JC036, JC037, JC038,JC039, JC040, JC041, JC042, JC043, JC044, JC045, JC046, JC142.

3,5-Di((E)-benzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC001)

1H NMR (400 MHz, CD3OD) δ 7.80 (br s, 2H), 7.38-7.50 (m, 10H), 4.91 (s,2H), 4.81 (s, 2H), 2.46 (t, J=7.5 Hz, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.02(s, 6H).

13C NMR (100 MHz, CD3OD) δ 186.4, 170.7, 137.7, 136.9, 134.6, 134.4,132.1, 131.9, 130.2, 130.1, 129.5, 129.4, 128.7, 128.5, 54.1, 46.3,43.5, 43.2, 29.9.

HR-APCI m/z calcd for C₂₄H₂₆N₂O₂ [M+H]=375.20725, found 375.20679.

2-(Dimethylamino)ethyl3,5-di((E)-benzylidene)-4-oxopiperidine-1-carboxylate (JC002)

¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (br s, 2H), 7.40-7.52 (m, 10H), 4.73(br s, 4H), 3.91 (t, J=5.4 Hz, 2H), 2.22 (t, J=5.5 Hz, 2H), 1.90 (s,6H).

¹³C NMR (100 MHz, DMSO-d₆) δ 186.2, 154.9, 136.8 (2C), 134.8 (2C), 132.9(2C), 130.9 (2C), 130.0 (2C), 129.3 (2C), 64.1, 57.6, 45.6 (2C), 45.3(2C).

3,5-Di((E)-benzylidene)-1-(3-(piperidin-1-yl)propanoyl)piperidin-4-one(JC003)

¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.80 (s, 1H), 7.43-7.37 (m,10H), 4.88 (s, 2H), 4.70 (s, 2H), 2.58 (t, J=7.2 Hz, 2H), 2.39 (t, J=7.1Hz, 2H), 2.23 (m, 4H), 1.49 (m, 4H), 1.36 (m, 2H).

¹³C NMR (100 MHz, CDCl₃) δ 186.8, 170.4, 138.5, 137.3, 134.6, 134.4,131.7, 131.8, 130.6, 130.2, 129.6 (2C), 128.9, 128.8, 54.3, 54.1, 46.3,43.6, 30.2, 25.4, 23.8.

3,5-Di((E)-benzylidene)-1-(3-morpholinopropanoyl)piperidin-4-one (JC004)

¹H NMR (400 MHz, CDCl₃) δ 7.85 (s, 1H), 7.81 (s, 1H), 7.36 (m, 10H),4.89 (s, 2H), 4.69 (s, 2H), 3.55 (m, 4H), 2.52 (t, J=7.0 Hz, 2H), 2.31(t, J=7.1 Hz, 2H), 2.19 (m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 186.7, 170.3, 138.6, 137.2, 134.6, 134.5,131.9, 131.7, 130.7, 130.2, 129.7 (2C), 128.9, 128.8, 66.7, 54.1, 53.3,46.3, 43.7, 30.4.

3,5-Di((E)-benzylidene)-1-(3-(diethylamino)propanoyl)piperidin-4-one(JC005)

¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.79 (s, 1H), 7.38 (m, 10H),4.88 (s, 2H), 4.70 (s, 2H), 2.63 (t, J=8.0 Hz, 2H), 2.27 (t, J=8.0 Hz,2H), 2.29 (q, J=7.2 Hz, 4H), 0.85 (t, J=7.1 Hz, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.7, 170.8, 138.4, 137.2, 134.6, 134.4,131.9, 131.7, 130.6, 130.2, 129.6, 129.5, 128.9, 128.8, 48.5, 46.8,46.4, 30.8, 11.6.

3,5-Di((E)-benzylidene)-1-(3-(4-methylpiperazin-1-yl)propanoyl)piperidin-4-one(JC006)

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.76 (s, 1H), 7.37 (m, 10H),4.85 (s, 2H), 4.65 (s, 2H), 2.50 (t, J=8.0 Hz, 2H), 2.26 (t, J=8.0 Hz,2H), 2.20 (m, 8H), 2.17 (s, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 186.6, 170.5, 138.5, 137.1, 134.5, 134.4,131.9, 131.7, 130.6, 130.1, 129.6 (2C), 128.8 (2C), 64.9, 53.7, 62.8,46.3, 43.6, 30.6.

3,5-Di((E)-benzylidene)-1-(3-(phenylthio)propanoyl)piperidin-4-one(JC012)

¹H NMR (400 MHz, CDCl₃) δ 7.84 (br s, 2H), 7.27 (m, 15H), 4.92 (s, 2H),4.64 (s, 2H), 3.09 (t, J=7.3 Hz, 2H), 2.45 (t, J=7.3 Hz, 2H).

¹³C NMR (100 MHz, CDCl₃) δ 186.6, 169.8, 138.6, 137.5, 135.5, 134.6,134.3, 131.5, 130.6, 130.1, 129.6, 129.5, 129.0, 128.9 (2C), 128.8 (2C),126.3, 46.2, 43.6, 32.8, 28.9.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-4-methoxybenzylidene)piperidin-4-one(JC013)

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.74 (s, 1H), 7.46 (d, J=8.0 Hz,2H), 7.35 (d, J=8.0 Hz, 2H), 6.96 (m, 4H), 4.91 (s, 2H), 4.73 (s, 2H),3.85 (s, 6H), 2.50 (t, J=7.4 Hz, 2H), 2.36 (t, J=7.4 Hz, 2H), 2.08 (s,6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.4, 170.4, 160.7 (2C), 137.9, 136.7,132.7, 132.1, 130.0, 129.7, 127.4, 127.1, 114.4, 114.3, 55.4, 54.9,46.3, 45.2, 43.5, 31.3.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-4-methylbenzylidene)piperidin-4-one(JC014)

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.73 (s, 1H), 7.25 (m, 8H), 4.84(s, 2H), 4.65 (s, 2H), 2.49 (t, J=7.4 Hz, 2H), 2.32 (m, 8H), 2.05 (s,6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.6, 170.1, 140.1, 140.0, 139.9, 138.3,137.2, 131.9, 131.6, 131.1, 130.9, 130.8, 130.3, 129.7 (2C), 129.6,129.5 (2C), 54.7, 46.3, 44.9, 43.6, 31.0, 21.4.

3,5-Bis((E)-4-chlorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC015)

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.76 (s, 1H), 7.38 (m, 8H), 4.87(s, 2H), 4.71 (s, 2H), 2.51 (t, J=7.4 Hz, 2H), 2.34 (t, J=7.3 Hz, 2H),2.09 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.1, 170.3, 137.0, 135.9, 135.8, 135.7,132.9, 132.8, 132.0 (2C), 131.8, 131.4, 129.2, 129.1, 54.8, 46.3, 45.1,43.3, 31.2.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-3,4-dimethylbenzylidene)piperidin-4-one(JC016)

¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.74 (s, 1H), 7.14 (m, 6H), 4.88(s, 2H), 4.68 (s, 2H), 2.51 (t, J=7.1 Hz, 2H), 2.33 (t, J=7.2 Hz, 2H),2.26 (s, 12H), 2.06 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.7, 170.2, 138.8 (2C), 138.6, 137.4,137.2, 136.9, 132.4 (2C), 132.1, 131.6, 131.0, 130.8, 130.2, 130.1,128.4, 127.6, 54.7, 46.4, 44.9, 43.7, 31.0, 19.9.

3,5-Bis((E)-3-chlorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC017)

¹H-NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.71 (s, 1H), 7.29 (m, 8H), 4.85(s, 2H), 4.69 (s, 2H), 2.49 (t, J=7.3 Hz, 2H), 2.31 (t, J=7.3 Hz, 2H),2.07 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.1, 170.5, 137.1, 136.2, 136.1, 135.9,134.9, 134.8, 132.7 (2C), 130.2 (2C), 129.8 (2C), 129.7 (2C), 128.5,128.1, 54.8, 46.3, 45.2, 43.4, 31.2.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-3-(trifluoromethyl)benzylidene)piperidin-4-one(JC018)

¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.84 (s, 1H), 7.62 (m, 8H), 4.89(s, 2H), 4.75 (s, 2H), 2.59 (t, J=7.3 Hz, 2H), 2.38 (t, J=7.3 Hz, 2H),2.13 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.9, 170.4, 136.9 (2C), 135.8, 135.2,135.0, 133.2, 132.9 (2C), 131.6 (q, J_(C—CF)=36 Hz), 131.4 (q,J_(C—CF)=36 Hz), 129.5, 129.4, 127.1, 126.6, 126.2, 126.1, 123.7 (q,J_(CF)=270 Hz, 2C), 54.7, 46.2, 45.0, 43.2, 31.1.

(3E,5E)-1-(3-(Dimethylamino)propanoyl)-3,5-bis(furan-2-ylmethylene)piperidin-4-one(JC019)

¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, 2H), 7.44 (m, 2H), 6.68 (m, 2H), 6.48(m, 2H), 4.97 (s, 2H), 4.91 (s, 2H), 2.56 (s, 4H), 2.13 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.6, 170.6, 151.7, 151.6, 145.8, 145.7,128.3, 127.9, 123.4, 121.9, 118.5, 118.0, 112.8, 112.6, 55.1, 46.1,45.3, 43.4, 31.6.

(3E,5E)-1-(3-(Dimethylamino)propanoyl)-3,5-bis(thiophen-2-ylmethylene)piperidin-4-one(JC020)

¹H NMR (400 MHz, CDCl₃) δ 7.98 (br s, 2H), 7.60 (m, 2H), 7.39 (m, 2H),7.17 (m, 2H), 4.95 (s, 2H), 4.82 (s, 2H), 2.62 (m, 4H), 2.19 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.2, 170.5, 138.3, 137.7, 134.1, 133.8,131.4, 131.0, 130.1, 129.1, 128.5, 128.4 (2C), 128.1, 54.9, 46.2, 45.4,43.1, 31.6.

(3E,5E)-1-(3-(Dimethylamino)propanoyl)-3,5-bis(pyridin-2-ylmethylene)piperidin-4-one(JC021)

¹H NMR (400 MHz, CDCl₃) δ 8.72 (t, J=4.8 Hz, 2H), 7.75 (m, 2H), 7.68 (s,1H), 7.64 (s, 1H), 7.49 (t, J=7.8 Hz, 2H), 7.23 (m, 2H), 5.38 (s, 2H),5.31 (s, 2H), 2.59 (m, 4H), 2.16 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 188.1, 170.8, 154.4 (2C), 149.9, 149.7,136.8, 136.3, 136.0, 135.6, 134.9, 132.8, 128.3, 127.6, 123.4, 123.0,55.1, 46.6, 45.3, 44.7, 31.5.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-4-(trifluoromethyl)benzylidene)piperidin-4-one(JC022)

¹H NMR (400 MHz, CDCl₃) δ 7.85 (br s, 2H), 7.68 (m, 4H), 7.54 (m, 4H),4.89 (s, 2H), 4.74 (s, 2H), 2.55 (t, J=7.3 Hz, 2H), 2.35 (t, J=7.4 Hz,2H), 2.10 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.0, 170.3, 137.8, 137.7, 136.8, 135.9,133.3 (2C), 131.4 (q, J_(C—CF)=33 Hz), 131.2 (q, J_(C—CF)=33 Hz), 130.5,130.2, 125.8, 125.7, 123.7 (q, J_(CF)=273 Hz, 2C), 54.7, 46.3, 44.9,43.2, 31.0.

HR-APCI m/z calcd for C₂₆H₂₄F₆N₂O₂ [M+H]=511.18202, found 511.18173.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-2-(trifluoromethyl)benzylidene)piperidin-4-one(JC023)

¹H NMR (400 MHz, CDCl₃) δ 7.97 (br s, 2H), 7.66 (m, 2H), 7.41 (m, 6H),4.55 (s, 2H), 4.41 (s, 2H), 2.40 (t, J=7.5 Hz, 2H), 2.14 (t, J=7.3 Hz,2H), 1.96 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.9, 170.4, 136.9, 135.9, 135.1, 135.0,133.2, 132.9 (2C), 131.9 (q, J_(C—CF)=32 Hz), 131.4 (q, J_(C—CF)=32 Hz),129.6, 129.4, 127.1 (2C), 126.6, 126.2, 126.1, 123.6 (q, J_(CF)=274 Hz,2C), 54.3, 45.9, 44.5, 42.9, 30.1.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-3-fluorobenzylidene)piperidin-4-one(JC024)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.34 (m, 8H), 4.85 (s, 2H),4.70 (s, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.3 Hz, 2H), 2.07 (s,6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.2, 170.3, 162.7 (d, J_(CF)=240 Hz) (2C),137.2, 136.5 (2C), 136.1, 132.6 (2C), 130.6, 130.4, 126.3, 125.9, 117.0(d, J_(C—CF)=22 Hz), 116.7 (d, J_(C—CF)=22 Hz) (2C), 116.5 (d,J_(C—CF)=19 Hz), 54.7, 46.3, 45.1, 43.4, 31.1.

¹⁹F NMR (376 MHz, CDCl₃) δ −111.4 (s, 1F), −112.0 (s, 1F).

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-2-fluorobenzylidene)piperidin-4-one(JC025)

¹H NMR (400 MHz, CDCl₃) δ 7.85 (s, 1H), 7.81 (s, 1H), 7.17 (m, 8H), 4.73(s, 2H), 4.54 (s, 2H), 2.44 (t, J=7.3 Hz, 2H), 2.25 (t, J=7.4 Hz, 2H),2.01 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.8, 170.3, 161.0 (d, J_(CF)=250 Hz), 160.5(d, J_(CF)=249 Hz), 133.6, 133.3, 131.6, 131.4, 131.0, 130.7 (2C),130.3, 124.4, 124.2, 122.5 (d, J_(C—CF)=13 Hz), 122.3 (d, J_(C—CF)=14Hz), 116.2 (d, J_(C—CF)=22 Hz), 115.9 (d, J_(C—CF)=22 Hz), 54.7, 46.5,45.0, 43.4, 31.0.

3,5-Bis((E)-4-chloro-3-fluorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC027)

¹H NMR (500 MHz, CD₃OD) δ 7.52 (m, 4H), 7.26 (m, 4H), 4.84 (s, 2H), 4.80(s, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.50 (t, J=7.3 Hz, 2H), 2.19 (s, 6H).

¹³C NMR (126 MHz, CD₃OD) δ 185.3, 170.5, 157.7 (d, J_(CF)=249 Hz), 157.6(d, J_(CF)=248 Hz), 135.2, 135.1, 134.9, 134.5, 133.0 (2C), 130.8,130.6, 126.9 (2C), 121.8 (d, J_(C—CF)=18 Hz), 121.6 (d, J_(C—CF)=18 Hz),117.8, 117.7, 54.1, 46.1, 43.4, 42.6, 29.4.

3,5-Bis((E)-3,5-dichlorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC028)

¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.56 (s, 1H), 7.40-7.10 (m, 6H),4.79 (s, 2H), 4.66 (s, 2H), 2.50 (t, J=7.4 Hz, 2H), 2.31 (t, J=7.2 Hz,2H), 2.08 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.4, 170.4, 137.1 (2C), 135.7 (2C), 135.4,134.7, 133.5 (2C), 129.6, 129.4, 128.4, 128.0, 54.8, 46.3, 45.2, 43.2,31.2.

HR-APCI m/z calcd for C₂₄H₂₂C₁₄N₂O₂ [M+H]=513.04841, found 513.04884.

3,5-Bis((E)-3,4-dimethoxybenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC029)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (s, 1H), 7.69 (s, 1H), 6.87 (m, 6H), 4.86(s, 2H), 4.69 (s, 2H), 3.85 (s, 12H), 2.44 (t, J=7.2 Hz, 2H), 2.30 ((t,J=7.1 Hz, 2H), 2.02 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.3, 170.4, 150.4 (2C), 149.1, 148.9,138.2, 137.1, 130.2, 129.9, 127.7, 127.4, 124.5, 123.5, 113.8, 113.6,111.2 (2C), 55.9 (2C), 54.9, 46.4, 45.2, 43.5, 31.4.

3,5-Bis((E)-2-chloro-3-(trifluoromethyl)benzylidene)-1-(3(dimethylamino)propanoyl)piperidin-4-one (JC030)

¹H NMR (400 MHz, CDCl₃) δ 7.97 (br s, 2H), 7.69 (m, 3H), 7.41 (m, 3H),4.68 (s, 2H), 4.51 (s, 2H), 2.47 (t, J=7.1 Hz, 2H), 2.25 (t, J=7.0 Hz,2H), 2.06 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.6, 170.3, 135.4 (2C), 134.9, 134.2, 133.9(2C), 133.3 (2C), 132.8, 132.7, 130.0 (q, J_(C—CF)=38 Hz), 129.4 (q,J_(C—CF)=38 Hz), 128.4, 128.1, 126.8 (2C), 122.6 (q, J_(CF)=272 Hz, 2C),54.7, 46.1, 45.1, 42.8, 31.2.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-4-fluorobenzylidene)piperidin-4-one(JC031)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.71 (s, 1H), 7.35 (m, 4H), 7.05(m, 4H), 4.80 (s, 2H), 4.65 (s, 2H), 2.47 (t, J=7.4 Hz, 2H), 2.30 (t,J=7.3 Hz, 2H), 2.03 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.2, 170.3, 163.2 (d, J_(CF)=250 Hz, 2C),137.2, 136.1, 132.6 (d, J_(C—C—CF)=7.9 Hz, 2C), 132.2 (d, J_(C—C—CF)=7.4Hz, 2C), 131.4, 131.3, 130.7, 130.5, 116.1 (d, J_(C—CF)=21 Hz, 2C),115.9 (d, J_(C—CF)=21 Hz, 2C), 54.8, 46.3, 45.1, 43.3, 31.0.

3,5-Bis((E)-3,4-dichlorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC032)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.46 (m, 4H), 7.25(m, 2H), 4.85 (s, 2H), 4.72 (s, 2H), 2.57 (t, J=7.2 Hz, 2H), 2.38 (t,J=7.2 Hz, 2H), 2.15 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.6, 170.3, 135.9, 135.0, 134.3, 134.1(2C), 133.8, 133.3, 133.1, 132.7 (2C), 132.0, 131.6, 131.0, 130.8,129.4, 129.1, 54.7, 46.3, 45.2, 43.2, 31.1.

3,5-Bis((E)-4-chloro-2-fluorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC033)

¹H NMR (400 MHz, CD₃OD) δ 7.77 (s, 2H), 7.46 (m, 2H), 7.27 (m, 4H), 4.78(s, 2H), 4.72 (s, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H),2.21 (s, 6H)

¹³C NMR (126 MHz, CDCl₃) δ 185.5, 170.0, 160.8 (d, J_(CF)=256 Hz), 160.3(d, J_(CF)=256 Hz), 136.8, 136.7, 133.6, 133.5, 131.4, 131.3, 130.1,129.5, 125.1, 124.9, 121.2 (d, J_(C—CF)=13 Hz), 120.7 (d, J_(C—CF)=13Hz), 117.2 (d, J_(C—CF)=25 Hz), 116.9 (d, J_(C—CF)=25 Hz), 54.6, 46.5,45.0, 43.4, 30.8.

3,5-Bis((E)-3-bromobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC034)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.49 (m, 4H), 7.40(m, 4H), 4.87 (s, 2H), 4.70 (s, 2H), 2.53 (t, J=7.3 Hz, 2H), 2.33 (t,J=7.2 Hz, 2H), 2.10 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 170.4, 137.1, 136.5, 136.3, 135.9(2C), 133.2, 132.6 (2C), 132.5, 130.5, 130.3, 128.9, 128.5, 123.1,122.8, 54.7, 46.3, 45.1, 43.4, 31.1.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-naphthalen-1-ylmethylene)piperidin-4-one(JC035)

¹H NMR (400 MHz, CDCl₃) δ 8.52 (br s, 2H), 7.94 (m, 6H), 7.51 (m, 8H),4.81 (s, 2H), 4.58 (s, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.09 (t, J=7.1 Hz,2H), 1.81 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.7, 170.1, 137.0, 135.9, 133.7, 133.6(2C), 133.4, 132.0, 131.8, 131.5, 130.2, 130.0, 128.8, 128.7, 127.3(2C), 127.1 (2C), 127.0, 126.8, 126.7, 126.4, 125.2, 125.1, 124.5, 54.5,46.4, 44.6, 43.6, 30.8.

3,5-Bis((E)-2-chlorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC036)

¹H NMR (400 MHz, CDCl₃) δ 7.97 (br s, 2H), 7.27 (m, 8H), 4.73 (s, 2H),4.53 (s, 2H), 2.49 (t, J=7.4 Hz, 2H), 2.26 (t, J=7.4 Hz, 2H), 2.07 (s,6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 170.2, 135.6, 135.2, 134.8, 134.7,133.1, 133.0, 132.8 (2C), 130.8, 130.5, 130.3 (2C), 130.2, 130.0, 126.8(2C), 54.6, 46.1, 44.9, 43.2, 30.9.

3,5-Bis((E)-4-bromobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC037)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.61 (m, 4H), 7.29(m, 4H), 4.85 (s, 2H), 4.70 (s, 2H), 2.59 (t, J=7.3 Hz, 2H), 2.40 (t,J=7.3 Hz, 2H), 2.16 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 170.0, 137.1, 136.2, 133.3, 133.1,132.2, 132.0, 131.9 (2C), 131.6 (2C), 124.3, 124.2, 54.6, 46.3, 45.0,43.3, 30.8.

1-(3-(Dimethylamino)propanoyl)-3,5-bis((E)-3-fluoro-4-methylbenzylidene)piperidin-4-one(JC038)

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.73 (s, 1H), 7.24 (m, 2H), 7.08(m, 4H), 4.89 (s, 2H), 4.72 (s, 2H), 2.59 (t, J=7.3 Hz, 2H), 2.40 (t,J=7.3 Hz, 2H), 2.32 (s, 6H), 2.15 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 170.1, 161.1 (d, J_(CF)=245 Hz, 2C),137.3 (2C), 136.2 (2C), 133.9 (dd, J_(C—C—CF)=6.6 Hz, J_(C—C—CF)=4.2Hz), 132.0 (2C), 131.7 (2C), 127.0 (dd, J_(C—C—CF)=6.4 Hz,J_(C—C—CF)=3.5 Hz), 126.4, 125.9, 116.7 (d, J_(C—CF)=20 Hz), 116.4 (d,J_(C—CF)=20 Hz), 54.7, 46.3, 44.9, 43.4, 30.9, 14.6 (2C).

Dimethyl3,3′-((1E,1′E)-(1-(3-(dimethylamino)propanoyl)-4-oxopiperidine-3,5-diylidene)bis(methaneylidene))dibenzoate (JC039)

¹H NMR (400 MHz, CDCl₃) δ 8.04 (m, 4H), 7.84 (s, 1H), 7.83 (s, 1H), 7.52(m, 4H), 4.89 (s, 2H), 4.73 (s, 2H), 3.91 (s, 6H), 2.44 (t, J=6.9 Hz,2H), 2.26 (t, J=7.0 Hz, 2H), 2.00 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.1, 170.4, 166.4, 166.2, 137.5, 136.2,134.8, 134.6, 134.5, 134.3, 132.6 (2C), 131.4, 130.9, 130.8, 130.5,129.1, 128.9, 54.8, 52.4 (2C), 46.4, 45.2, 43.4, 31.2.

(3E,5E)-1-(3-(Dimethylamino)propanoyl)-3,5-bis((1-methyl-1H-pyrrol-2-yl)methylene)piperidin-4-one(JC040)

¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 2H), 6.80 (m, 2H), 6.54 (m, 1H), 6.38(m, 1H), 6.21 (m, 2H), 4.75 (s, 2H), 4.62 (s, 2H), 3.68 (s, 6H), 2.49(m, 4H), 2.10 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 184.9, 170.5, 128.9, 128.6, 127.7 (2C),126.5, 126.3, 124.2, 123.2, 116.2, 115.2, 110.1, 110.0, 55.1, 46.6,45.4, 43.5, 34.5, 34.4, 31.6.

(3E,5E)-3,5-Bis((1-benzyl-1H-indol-2-yl)methylene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one (JC041)

¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 2H), 7.94 (m, 2H), 7.31 (m, 14H),7.14 (m, 4H), 5.41 (s, 4H), 4.87 (s, 2H), 4.71 (s, 2H), 2.53 (t, J=7.1Hz, 2H), 2.47 (t, J=7.1 Hz, 2H), 2.06 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.2, 170.2, 136.3, 130.8, 130.1, 129.8,129.0, 128.9, 128.0, 127.6, 126.9, 126.7, 123.6, 123.4, 121.4, 121.3,119.6, 119.4, 115.0, 112.2, 110.3, 54.9, 50.8, 47.0, 45.3, 44.2, 31.2.

(3E,5E)-3,5-Bis(cyclohexylmethylene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC042)

¹H NMR (400 MHz, CDCl₃) δ 6.72 (s, 1H), 6.69 (s, 1H), 4.50 (s, 2H), 4.38(s, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.53 (t, J=7.1 Hz, 2H), 2.24 (s, 6H),1.68 (m, 10H), 1.24 (m, 12H).

¹³C NMR (100 MHz, CDCl₃) δ 186.6, 170.0, 147.0, 145.7, 129.9, 129.6,55.0, 45.4, 44.9, 41.6, 37.4, 37.2, 31.9, 31.7, 31.5, 25.7, 25.6, 25.3.

(3E,5E)-3,5-Bis(benzofuran-2-ylmethylene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC043)

¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 4H), 7.52 (m, 2H), 7.37 (m, 2H), 7.25(m, 2H), 7.06 (m, 2H), 5.22 (s, 2H), 5.16 (s, 2H), 2.72 (app. s, 4H),2.21 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.5, 170.6, 156.2, 156.1, 153.0, 152.8,131.1, 130.4, 128.1, 127.9, 127.0, 126.8, 124.0, 123.8, 123.5, 122.6,122.1, 121.9, 115.1, 114.5, 111.8, 111.5, 55.0, 46.3, 45.2, 43.9, 31.2.

3,5-Bis((E)-3,5-difluorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC044)

¹H NMR (400 MHz, CDCl₃) δ 7.83 (br s, 2H), 7.43 (s, 1H), 7.30 (s, 1H),6.96 (s, 2H), 4.75 (s, 2H), 4.58 (s, 2H), 2.57 (t, J=7.4 Hz, 2H), 2.37(t, J=7.4 Hz, 2H), 2.14 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.7, 170.2, 151.1 (dd, =252.5 Hz,J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=252.5 Hz, J_(C—CF)=12 Hz, 2C),136.7, 134.3, 133.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.5 Hz, 2C),131.8, 130.3, 129.6 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.5 Hz, 2C),118.8 (d, J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=20 Hz, 2C), 54.6,46.5, 44.9, 43.3, 30.8.

3,5-Bis((E)-2,3-difluorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC045)

¹H NMR (400 MHz, CDCl₃) δ 7.83 (br s, 2H), 7.12 (m, 6H), 4.75 (s, 2H),4.58 (s, 2H), 2.48 (t, J=7.4 Hz, 2H), 2.29 (t, J=7.4 Hz, 2H), 2.07 (s,6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.5, 170.4, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C),134.2, 130.1, 129.4, 125.5, 124.6 (2C), 124.3 (2C), 118.6 (d,J_(C—CF)=17 Hz, 2C), 118.5 (d, J_(C—CF)=17 Hz, 2C), 54.7, 46.6, 45.1,43.4, 31.0.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(pyrrolidin-1-yl)propanoyl)piperidin-4-one(JC046)

¹H NMR (400 MHz, CDCl₃) δ 7.71 (br s, 2H), 7.21 (m, 6H), 4.83 (s, 2H),4.74 (s, 2H), 2.92 (t, J=7.3 Hz, 2H), 2.65 (t, J=7.3 Hz, 2H), 2.62 (m,4H), 1.83 (m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 185.9, 169.6, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C),136.2, 135.7, 131.9 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.5 Hz, 2C),131.5, 131.3, 127.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=4.2 Hz, 2C),119.2 (d, J_(C—CF)=17 Hz, 2C), 118.4 (d, J_(C—CF)=17 Hz, 2C), 64.0,51.2, 46.4, 43.1, 31.2, 29.7, 23.4, 22.8.

3,5-Bis((E)-3,4-difluorobenzylidene)piperidin-4-one (142)

¹H NMR (400 MHz, CDCl₃) δ 7.67 (br s, 2H), 7.17 (m, 6H), 4.11 (br s 4H).

¹³C NMR (100 MHz, CDCl₃) δ 187.3, 150.7 (dd, J_(CF)=251 Hz, J_(C—CF)=13Hz, 2C), 150.3 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C), 135.3 (2C),133.9 (2C), 132.1 (dd, J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=4.1 Hz, 2C), 127.1(dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.5 Hz, 2C), 119.0 (d, J_(C—CF)=18Hz, 2C), 117.6 (d, J_(C—CF)=18 Hz, 2C), 47.9.

General Procedure B:

Compound JC049-JC053 and their analogues were generally prepared byreaction of 3,4-difluoro-benzaldehyde, with piperidin-4-one hydrogenchloride in the present of 40% aq. sodium hydroxide to give3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one. Acylation of this3,5-bis((E)-3,4-difluorobenzyl-idene)piperidin-4-one with acryloylchloride under basic conditions afforded the 1-acryloyl3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one. Michael addition ofan amine, e.g., diethylamine, afforded the1-(3-(dialkylamino)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one,e.g.,1-(3-(diethyl-amino)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one

Preparation of JC049:

To the mixture of piperidin-4-one hydrogen chloride (135.59 mg, 1 mmol,1.0 equiv.) and methanol (2.0 mL) in a round bottom flask was addeddropwise 40% aqueous sodium hydroxide (1.0 mL) and the reaction mixturewas stirred for 5 min. To this mixture was added3,4-difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.). The reactionmixture was then allowed to stir at 21° C. for 3 h, at which time ayellow solid had precipitated. The precipitate thus obtained wasfiltered, washed with water and cold methanol and dried to get the purepiperidone product (285 mg, 80% yield).

A mixture of 3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (173.7mg, 0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (105 μL, 0.75mmol, 1.5 equiv.) in dichloromethane was maintained at 0° C. (ice bath).To this cooled mixture was added dropwise acryloyl chloride (61 μL, 0.75mmol, 1.5 equiv.). After the complete addition of the acryloyl chloride,the reaction mixture was slowly warmed up to 21° C. and stirred for afurther 4 h. After completion of the reaction, the solvent wasevaporated and the residue thus obtained was washed with water, filteredand dried. The crude amide product was pure enough to be used for thenext step.

A mixture of the crude1-acryloyl-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (200.7mg, 0.5 mmol, 1.0 equiv.), 2,6-bis(1,1-dimethylethyl)-4-methylphenol(1.1 mg, 0.005 mmol, 1%) and diethylamine (54.9 mg, 0.75 mmol, 1.5equiv.) in 1.0 mL anhydrous THF was heated to 65° C. under argon for 12h. The solvent was evaporated and flash chromatography of the residue(gradient elution 10% methanol/EtOAc-20% methanol/EtOAc) gave thedesired compound JC049 (151.8 mg, 64% yield) as a yellow solid.

The following compounds were synthesized by procedure B: JC026, JC047,JC048, JC049, JC050, JC051, JC052, JC069, JC079, JC096.

1-(3-(Diethylamino)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC049)

¹H NMR (400 MHz, d₆-Acetone) δ 7.65 (br s, 2H), 7.55 (m, 2H), 7.43 (m,4H), 4.90 (br s, 4H), 2.62 (t, J=7.2 Hz, 2H), 2.36 (m, 6H), 0.85 (t,J=7.1 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.0, 170.7, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C),136.3, 135.4, 132.2, 132.1, 131.5, 131.3, 127.2, 126.8, 119.2 (d,J_(C—CF)=18 Hz), 118.9 (d, J_(C—CF)=18 Hz), 118.1 (d, J_(C—CF)=18 Hz),117.9 (d, J_(C—CF)=17 Hz), 48.6, 47.0, 46.4, 43.1, 31.0, 11.4.

¹⁹F NMR (376 MHz, CDCl₃) δ −133.9 (m, 1F), −134.3 (m, 1F), −135.5 (m,1F), −136.1 (m, 1F).

HR-APCI m/z calcd for C₂₆H₂₆F₄N₂O₂ [M+H]=475.20087, found 475.20080.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC026)

¹H NMR (400 MHz, d₆-Acetone) δ 7.66 (br s, 2H), 7.58 (m, 2H), 7.44 (m,4H), 4.91 (br s, 4H), 2.41 (s, 4H), 2.00 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.9, 170.3, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=13 Hz) (2C), 150.4 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz) (2C),136.3, 135.4, 132.1 (2C), 131.5, 131.3, 127.2, 126.8, 119.2 (d,J_(C—CF)=18 Hz), 118.9 (d, J_(C—CF)=17 Hz), 118.1 (d, J_(C—CF)=17 Hz),117.9 (d, J_(C—CF)=17 Hz), 54.7, 46.3, 45.2, 43.1, 31.2.

¹⁹F NMR (376 MHz, CDCl₃) δ −133.8 (m, 1F), −134.3 (m, 1F), −135.5 (m,1F), −136.1 (m, 1F).

HR-APCI m/z calcd for C₂₄H₂₂F₄N₂O₂ [M+H]=447.16957, found 447.16993.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-morpholinopropanoyl)piperidin-4-one(JC047)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 2H), 7.18 (m, 6H), 4.85 (s, 2H),4.69 (s, 2H), 3.60 (t, J=4.8 Hz, 4H), 2.57 (t, J=7.4 Hz, 2H), 2.36 (t,J=7.4 Hz, 2H), 2.29 (t, J=4.8 Hz, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 185.8, 170.4, 151.1 (dd, =253 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=253 Hz, J_(C—CF)=14 Hz, 2C), 136.4, 135.3,132.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=4.1 Hz, 2C), 131.4, 127.2 (dd,J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=4.1 Hz, 2C), 126.9, 119.2 (d, J_(C—CF)=18Hz, 2C), 118.0 (d, J_(C—CF)=17 Hz, 2C), 64.0, 51.2, 46.4, 43.1, 31.2,29.7, 23.4, 22.8.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(piperidin-1-yl)propanoyl)piperidin-4-one(JC048)

¹H NMR (400 MHz, CDCl₃) δ 7.70 (s, 1H), 7.67 (s, 1H), 7.19 (m, 6H), 4.82(s, 2H), 4.69 (s, 2H), 2.58 (t, J=7.4 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H),2.26 (m, 4H), 1.49 (m, 4H), 1.37 (m, 2H).

¹³C NMR (100 MHz, CDCl₃) δ 185.9, 170.6, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C),136.2, 135.3, 132.2, 131.5 dd, J_(C—C—CF)=5.7 Hz, J_(C—C—CF)=4.1 Hz,2C), 127.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.4 Hz, 2C), 126.2, 118.8(d, J_(C—CF)=18 Hz, 2C), 117.4 (d, J_(C—CF)=18 Hz, 2C), 54.4, 46.3,43.1, 30.5, 25.6, 23.9.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(4-methylpiperazin-1-yl)propanoyl)piperidin-4-one(JC050)

¹H NMR (400 MHz, CDCl₃) δ 7.71 (br s, 2H), 7.16 (m, 6H), 4.84 (s, 2H),4.69 (s, 2H), 2.60 (t, J=7.4 Hz, 2H), 2.37 (m, 10H), 2.25 (s, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 186.0, 170.4, 151.1 (dd, =254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C), 136.4, 135.3,132.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.4 Hz, 2C), 131.4, 127.2 (dd,J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.4 Hz, 2C), 126.9, 118.7 (d, J_(C—CF)=20Hz, 2C), 117.6 (d, J_(C—CF)=20 Hz, 2C), 54.6, 53.5, 52.6, 46.3, 45.6,30.5.

1-(3-(4-Benzylpiperazin-1-yl)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC051)

¹H NMR (400 MHz, CDCl₃) δ 7.70 (br s, 2H), 7.23 (m, 11H), 4.83 (s, 2H),4.68 (s, 2H), 3.45 (s, 2H), 2.58 (t, J=7.4 Hz, 2H), 2.35 (m, 10H).

¹³C NMR (100 MHz, CDCl₃) δ 185.9, 170.5, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=13 Hz, 2C),137.9, 136.3, 135.3, 132.2, 131.4 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8Hz, 2C), 129.2, 128.2, 127.1, 127.2 (dd, J_(C—C—CF)=5.8 Hz,J_(C—C—CF)=3.4 Hz, 2C), 126.9, 118.6 (d, J_(C—CF)=20 Hz, 2C), 117.5 (d,J_(C—CF)=20 Hz, 2C), 62.9, 53.7, 53.0, 52.2, 46.3, 43.1, 30.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-((2-hydroxyethyl)(methyl)amino)propanoyl)piperidin-4-one (JC052)

¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.70 (s, 1H), 7.21 (m, 6H), 4.86(s, 2H), 4.70 (s, 2H), 3.56 (t, J=5.4 Hz, 2H), 2.79 (s, 1H), 2.67 (t,J=6.7 Hz, 2H), 2.46 (t, J=5.4 Hz, 2H), 2.36 (t, J=6.7 Hz, 2H), 2.16 (s,3H).

¹³C NMR (100 MHz, CDCl₃) δ 185.8, 170.6, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, =255 Hz, J_(C—CF)=13 Hz, 2C), 136.3,135.2, 132.2 (dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=4.2 Hz, 2C), 131.3,127.2 (dd, J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.8, 119.3 (d,J_(C—CF)=17 Hz), 118.9 (d, J_(C—CF)=17 Hz), 118.2 (d, J_(C—CF)=17 Hz),117.9 (d, J_(C—CF)=17 Hz), 60.0, 58.6, 52.1, 46.2, 43.2, 42.0, 30.6.

1-(3-(Benzyl)methyl)amino)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC069)

¹H NMR (400 MHz, CDCl₃) δ 7.69 (br s, 2H), 7.20 (m, 11H), 4.83 (s, 2H),4.64 (s, 2H), 3.36 (s, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz,2H), 2.05 (s, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 185.9, 170.7, 150.9 (dd, J_(CF)=255 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C),138.6, 136.2 (2C), 135.2 (2C), 131.8 (dd, J_(C—C—CF)=6.4 Hz,J_(C—C—CF)=4.2 Hz, 2C), 128.9, 128.3, 127.1, 126.8 (dd, J_(C—C—CF)=5.9Hz, J_(C—C—CF)=3.8 Hz, 2C), 119.3 (d, J_(C—CF)=17 Hz), 119.0 (d,J_(C—CF)=17 Hz), 118.1 (d, J_(C—CF)=17 Hz), 117.5 (d, J_(C—CF)=18 Hz),62.4, 53.0, 46.4, 43.1, 42.2, 31.6.

(E)-3-(3,4-Difluorobenzylidene)-1-(3-(dimethylamino)propanoyl)piperidin-4-one(JC079)

¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.21 (m, 3H), 4.80 (s, 2H), 3.85(t, J=6.3 Hz, 2H), 2.73 (m, 4H), 2.62 (t, J=6.3 Hz, 2H), 2.31 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 196.0, 170.4, 150.9 (dd, J_(CF)=254 Hz,J_(C—CF)=13 Hz), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=13 Hz), 135.6, 131.7(dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=4.2 Hz), 127.3 (dd, J_(C—C—CF)=6.4Hz, J_(C—C—CF)=4.2 Hz), 125.5, 118.4 (d, J_(C—CF)=17 Hz), 117.6 (d,J_(C—CF)=17 Hz), 55.0, 45.4, 42.7, 42.0, 39.2, 29.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(4-(4-fluorophenyl)piperazin-1yl)propanoyl)piperidin-4-one (JC096)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (br s, 2H), 7.19 (m, 6H), 6.95 (m, 2H),6.82 (m, 2H), 4.66 (br s, 4H), 3.13 (t, J=6.4 Hz, 2H), 3.03 (m, 4H),2.80 (t, J=6.4 Hz, 2H), 2.56 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 184.8, 170.1, 157.3 (d, =240 Hz), 151.2 (dd,J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C), 150.5 (dd, J_(CF)=251 Hz,J_(C—CF)=13 Hz, 2C), 147.6 (d, J_(C—C—CF)=11 Hz), 136.5, 134.1 (2C),133.0 (dd, J_(C—C—CF)=6.6 Hz, J_(C—C—CF)=3.5 Hz, 2C), 131.2 (2C), 127.2(dd, J_(C—C—CF)=6.6 Hz, J_(C—C—CF)=3.5 Hz, 2C), 118.9 (d, J_(C—CF)=17Hz, 2C), 117.8 (d, J_(C—CF)=18 Hz, 2C), 115.5 (d, J_(C—CF)=20 Hz), 53.0,51.8, 50.0, 49.9, 46.7.

General Procedure C:

Compounds JC070, JC080 and their analogues were generally prepared byreaction of 3,4-difluoro-benzaldehyde, with tert-butyl(4-oxocyclohexyl)carbamate in the present of 20% aq. sodium hydroxide togive tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate. The Bocprotecting group was deprotected with TFA. Acylation of the4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclo-hexan-1-one withacryloyl chloride under basic conditions afforded theN-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)acrylamide.Michael addition of an amine, e.g., dimethylamine, afforded theN-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(dialkylamino)propanamide,e.g.,N-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(dimethylamino)propanamide

Preparation of JC070:

To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (213.28 mg, 1mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round bottom flask was addeddropwise 20% aqueous sodium hydroxide (1.0 mL) and the reaction mixturewas stirred for 5 min. To this mixture was added3,4-difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.). The reactionmixture was then allowed to stir at 21° C. for 5 h, at which time ayellow solid had precipitated. The precipitate thus obtained wasfiltered, washed with water and cold ethanol and dried to get the purebis(arylmethylidene)cyclohexanone product (360 mg, 78% yield).

Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7mg, 0.5 mmol) in methylene chloride (5.0 ml) at 21° C. and the reactionmixture was stirred overnight at 21° C. The reaction solvent wasdistilled off under reduced pressure and the resulting residue waspoured into a 1N aqueous sodium hydroxide solution and extracted withethyl acetate and chloroform. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

A mixture of4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg,0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (70 μL, 0.5 mmol, 1.0equiv.) in dichloromethane was maintained at 0° C. (ice bath). To thiscooled mixture was added dropwise acryloyl chloride (40 μL, 0.5 mmol,1.0 equiv.). After the complete addition of the acryloyl chloride, thereaction mixture was slowly warmed up to 21° C. and stirred over night.After completion of the reaction, the solvent was evaporated and theresidue thus obtained was washed with water, filtered and dried. Thecrude amide product was pure enough to be used for the next step.

A mixture of the crudeN-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)acrylamide(207.7 mg, 0.5 mmol, 1.0 equiv.),2,6-bis(1,1-dimethylethyl)-4-methylphenol (1.1 mg, 0.005 mmol, 1%) anddimethylamine (2N in THF) (0.375 mL, 0.75 mmol, 1.5 equiv.) in 1.0 mLanhydrous THF was heated to 65° C. under argon for 12 h. The solvent wasevaporated and flash chromatography of the residue (gradient elution 10%methanol/EtOAC-20% methanol/EtOAc) gave the desired compound JC070(170.4 mg, 74% yield) as a yellow solid.

The following compounds were synthesized by procedure C: JC070, JC080,JC097.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(dimethylamino)propanamide(JC070)

¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 7.80 (s, 2H), 7.22 (m, 6H), 4.39(m, 1H), 3.14 (dd, J=16.3 Hz, J=5.7 Hz, 2H), 3.01 (bd, J=15.7 Hz, 2H),2.39 (t, J=5.5 Hz, 2H), 2.23 (t, J=5.5 Hz, 2H), 2.11 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.9, 172.4, 150.6 (dd, =254 Hz, J_(CF)=13Hz, 2C), 150.2 (dd, J_(CF)=250 Hz, J_(CF)=13 Hz, 2C), 137.6 (2C), 132.9(2C), 132.3 (dd, J_(C—C—CF)=5.7 Hz, J_(C—C—CF)=4.3 Hz, 2C), 126.9 (dd,J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.4 Hz, 2C), 118.9 (d, J_(C—CF)=18 Hz)(2C), 117.6 (d, J_(C—CF)=17 Hz) (2C), 54.9, 53.5, 44.2, 42.8 (2C), 33.3(2C), 32.4.

¹⁹F NMR (376 MHz, CDCl₃) δ −135.2 (m, 2F), −136.6 (m, 2F).

HR-APCI m/z calcd for C₂₅H₂₄F₄N₂O₂ [M+H]=461.18522, found 461.18461.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(piperidin-1-yl)propanamide(JC080)

¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 7.79 (s, 2H), 7.22 (m, 6H), 4.37(m, 1H), 3.12 (bd, J=15.8 Hz, 2H), 3.04 (dd, J=16.2 Hz, J=6.0 Hz, 2H),2.48 (t, J=5.6 Hz, 2H), 2.39 (m, 4H), 2.31 (t, J=5.8 Hz, 2H), 1.50 (m,6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 172.1, 150.6 (dd, =252 Hz, J_(C—CF)=13Hz, 2C), 150.2 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C), 137.6 (2C),132.9 (2C), 132.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.1 Hz 2C), 127.1(dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.4 Hz 2C), 118.8 (d, J_(C—CF)=18 Hz,2C), 117.6 (d, J_(C—CF)=18 Hz, 2C), 54.3, 53.7, 43.3, 33.6, 31.5, 25.4,23.8.

HR-APCI m/z calcd for C₂₈H₂₈F₄N₂O₂ [M+H]=501.21652, found 501.21594.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-(dimethylamino)-N-methylpropanamide(JC097)

¹H NMR (500 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.20 (m, 6H), 4.77 (m, 1H),3.04 (s, 3H), 2.98 (dd, J=16.3 Hz, J=5.8 Hz, 2H), 2.92 (bd, J=15.7 Hz,2H), 2.62 (t, J=5.7 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H), 2.25 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 171.7, 150.5 (dd, J_(CF)=255 Hz,J_(CF)=13 Hz, 2C), 150.2 (dd, J_(CF)=255 Hz, J_(CF)=13 Hz, 2C), 137.4,136.8, 133.9 (2C), 132.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.3 Hz, 2C),127.1 (dd, J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.8 Hz, 2C), 118.8 (d,J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=17 Hz, 2C), 54.9, 49.1, 45.5,32.6, 31.2, 30.3.

General Procedure D:

The compounds were generally prepared by reaction of the correspondingaldehydes, e.g., 3,4-difluorobenzaldehyde, with tert-butyl(4-oxocyclohexyl)carbamate in the present of 20% aq. sodium hydroxide togive tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate. TFAdeprotected Boc group. Benzoylation of4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one with4-(2-(dialkylamino)ethoxy)benzoyl chloride under base condition affordedtheN-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)ethoxy)benzamide.

Compounds JC081-JC087 and their analogues were generally prepared byreaction of the 3,4-difluorobenzaldehyde, with tert-butyl(4-oxocyclohexyl)carbamate in the present of 20% aq. sodium hydroxide togive tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate. The Bocprotecting group was deprotected with TFA. Benzoylation of4-amino-2,6-bis((E)-3,4-difluoro-benzylidene)cyclohexan-1-one with4-(2-(dialkylamino)ethoxy)benzoyl chloride under basic conditionsafforded the desiredN-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)-ethoxy)benzamide

Preparation of JC081:

To the mixture of tert-butyl (4-oxocyclohexyl)carbamate (213.28 mg, 1mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round bottom flask was addeddropwise 20% aqueous sodium hydroxide (1.0 mL) and the reaction mixturewas stirred for 5 min. To this mixture was added3,4-difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.). The reactionmixture was then allowed to stir at 21° C. for 5 h, at which time ayellow solid had precipitated. The precipitate thus obtained wasfiltered, washed with water, cold ethanol and dried to get the purebis(arylmethylidene)cyclohexanone product (360 mg, 78% yield).

Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7mg, 0.5 mmol) in methylene chloride (5.0 ml) at 21° C. and the reactionmixture was stirred overnight at 21° C. The reaction solvent wasdistilled off under reduced pressure and the resulting residue waspoured into a 1N aqueous sodium hydroxide solution and extracted withethyl acetate and chloroform. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain 4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

The mixture of4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg,0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (70 μL, 0.5 mmol, 1.0equiv.) in dichloromethane was maintained at 0° C. (ice bath). To thiscooled mixture was added dropwise 4-(2-(dimethylamino)ethoxy)benzoylchloride (113.8 mg, 0.5 mmol, 1.0 equiv., synthesized as describedbelow) in 2.0 mL dichloromethane. After the complete addition of the4-(2-(dimethylamino)ethoxy)benzoyl chloride, the reaction mixture wasslowly warmed up to 21° C. and stirred overnight. After completion ofthe reaction, the solvent was evaporated and the residue was stirred insat. aqueous K₂CO₃ for 4 h. The mixture was extracted with ethyl acetateand dichloromethane three times. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydroussodium sulfate. The solvent was evaporated and flash chromatography ofthe residue (gradient elution 5% methanol/EtOAC-10% methanol/EtOAc) gavethe desired compound JC081 (226.5 mg, 82% yield) as a yellow solid.

Synthesis of 4-(2-(dimethylamino)ethoxy)benzoyl chloride Method 1

To a round bottom flask with a stir-bar were added methyl4-hydroxybenzoate (3.043 g, 20 mmol, 1.0 equiv.),2-chloro-N,N-dimethylethylamine hydrochloride (3.457 g, 24 mmol, 1.2equiv.), potassium carbonate (6.081 g, 44 mmol, 2.2 equiv.) and 30 mLisopropyl acetate. The mixture was heated at 75° C. for 24 h, at whichtime all the methyl 4-hydroxybenzoate was consumed. Deionized water (30mL) was then added to dissolve the potassium carbonate. The organic andaqueous phases were separated. The organic layer was washed with 30 mLwater. The organic layer was washed with a saturated aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Thesolvent was evaporated and flash chromatography of the residue (gradientelution 5% methanol/EtOAc-10% methanol/EtOAc) gave the product, methyl4-(2-(dimethylamino)ethoxy)benzoate (2.0 g, 45% yield), as a lightyellow oil.

Methyl 4-(2-(dimethylamino)ethoxy)benzoate (1.116 g, 5.0 mmol, 1.0equiv.) was dissolved in 2.5 mL ethanol and added to a solution ofsodium hydroxide (0.4 g) in 2.5 mL of deionized water. The mixture washeated under reflux for 2 h. The ethanol was removed in vacuo and theaqueous solution was acidified with conc. HCl at 5-6° C. The solid wascollected, treated with cold water, filtered and dried at 55-60° C. invacuo to give 4-(2-(dimethylamino)ethoxy)benzoic acid hydrogen chlorideas a white sold (982.8 mg, 80% yield).

To a stirred mixture of 4-(2-(dimethylamino)ethoxy)benzoic acid hydrogenchloride (245.7 mg, 1.0 mmol) was added thionyl chloride (2.5 mL). Themixture was heated under reflux for 4 h. The thionyl chloride wasremoved in vacuo and the product dried to give4-(2-(dimethylamino)ethoxy)benzoyl chloride, which was enough pure to beused for the next step.

The following compounds were synthesized by procedure D: JC064, JC065,JC066, JC067, JC081, JC082, JC083, JC084, JC085, JC086, JC087, JC099,JC100, JC102, JC103, JC104, JC105, JC106, JC109, JC110, JC111, JC112,JC113, JC114, JC115, JC116, JC117, JC118, JC122, JC123, JC124, JC125,JC126, JC127, JC128, JC131, JC132, JC133, JC134, JC135, JC144.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)ethoxy)benzamide(JC081)

¹H NMR (400 MHz, CDCl₃) δ 7.78 (br s, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.22(m, 6H), 6.89 (d, J=8.8 Hz, 2H), 6.01 (d, J=7.2 Hz, 1H), 4.48 (m, 1H),4.10 (t, J=5.6 Hz, 2H), 3.26 (bd, J=15.8 Hz, 2H), 3.07 (dd, J=16.3 Hz,J=5.8 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.36 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.9, 166.6, 161.6, 150.7 (dd, =254 Hz,J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz, 2C),137.9 (2C), 132.7 (2C), 132.2 (dd, J_(C—C—CF)=5.7 Hz, J_(C—C—CF)=4.1 Hz,2C), 128.7 (2C), 127.1 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.4 Hz, 2C),126.3, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.7 (d, J_(C—CF)=18 Hz, 2C),114.4 (2C), 65.9, 58.1, 45.8, 44.6, 33.8

HR-APCI m/z calcd for C₃₁H₂₈F₄N₂O₃ [M+H]=553.21143, found 553.21034.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(dimethylamino)ethoxy)benzoyl)piperidin-4-one(JC064)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.15 (m, 8H), 6.64 (d, J=8.8Hz, 2H), 4.79 (br s, 4H), 3.98 (t, J=5.7 Hz, 2H), 2.72 (t, J=5.7 Hz,2H), 2.34 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 169.8, 164.2, 151.1 (dd, J_(CF)=253Hz, J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=249 Hz, J_(C—CF)=13 Hz, 2C),132.6, 132.4 (2C), 132.1, 131.9 (2C), 131.3, 128.3, 122.2, 121.8, 121.5,119.1 (d, J_(C—CF)=18 Hz, 2C), 117.9 (d, J_(C—CF)=17 Hz, 2C), 114.5,114.4, 65.9, 65.8, 57.8, 45.5, 29.7.

HR-APCI m/z calcd for C₃₀H₂₆F₄N₂O₃ [M+H]=539.19578, found 539.19473.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(pyrrolidin-1-yl)ethoxy)benzoyl)piperidin-4-one(JC065)

¹H NMR (400 MHz, CDCl₃) δ 7.75 (br s, 2H), 7.19 (m, 8H), 6.65 (d, J=8.8Hz, 2H), 4.81 (br s, 4H), 4.03 (t, J=5.9 Hz, 2H), 2.89 (t, J=5.8 Hz,2H), 2.63 (m, 4H), 1.83 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 186.3, 170.4, 160.5, 150.9 (dd, J_(CF)=254Hz, J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),135.8 (2C), 132.4 (2C), 131.4 (2C), 129.0, 127.0 (2C), 125.9, 119.0 (d,J_(C—CF)=17 Hz, 2C), 117.8 (d, J_(C—CF)=17 Hz, 2C), 114.0, 67.0, 54.8,54.7, 23.5.

1-(3-(Azepan-1-yl)propanoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-oneone(JC066)

¹H NMR (400 MHz, CDCl₃) δ 7.70 (s, 2H), 7.30 (m, 6H), 4.83 (s, 2H), 4.76(s, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.89 (m, 4H), 2.76 (t, J=7.0 Hz, 2H),1.75 (m, 4H), 1.62 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 186.0, 169.5, 150.9 (dd, J_(CF)=254 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=13 Hz, 2C),136.3, 135.8, 132.2 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.4 Hz, 2C),131.5, 127.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.6 Hz, 2C), 126.9,119.3 (d, J_(C—CF)=17 Hz, 2C), 118.4 (d, J_(C—CF)=17 Hz), 118.0 (d,J_(C—CF)=17 Hz), 55.2, 53.2, 46.3, 43.1, 29.7, 26.8, 25.4.

1-Acryloyl-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (JC067)

¹H NMR (400 MHz, CDCl₃) δ 7.71 (br s, 2H), 7.21 (m, 6H), 6.25 (m, 2H),5.62 (dd, J=10.0, 2.3 Hz, 1H), 4.84 (br s, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 185.8, 165.5, 150.9 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),136.4, 135.4, 132.0 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.4 Hz, 2C),131.4 (2C), 129.5, 127.1 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.4 Hz, 2C),126.9, 119.0 (d, J_(C—CF)=18 Hz, 2C), 117.2 (d, J_(C—CF)=18 Hz, 2C),46.5, 43.6.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(piperidin-1-yl)ethoxy)benzoyl)piperidin-4-one(JC082)

¹H NMR (500 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.12 (m, 8H), 6.62 (d, J=8.6Hz, 2H), 4.79 (br s, 4H), 4.03 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.8 Hz,2H), 2.44 (m, 4H), 1.63 (m, 4H), 1.43 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 170.5, 160.5, 151.0 (dd, J_(CF)=255Hz, J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz, 2C),135.9 (2C), 132.4 (2C), 131.4 (dd, J_(C—C—CF)=5.4 Hz, J_(C—C—CF)=4.2 Hz2C), 129.0 (2C), 126.9 (2C), 125.9, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.9(d, J_(C—CF)=18 Hz, 2C), 114.1 (2C), 65.9, 57.7, 55.0, 25.8, 24.1.

HR-APCI m/z calcd for C₃₃H₃₀F₄N₂O₃ [M+H]=579.22708, found 579.22644.

1-(3-Chloro-4-(2-(dimethylamino)ethoxy)benzoyl)-3,5-bis((E)-3,4difluorobenzylidene) piperidin-4-one (JC083)

¹H NMR (500 MHz, CDCl₃) δ 7.75 (br s, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.17(m, 6H), 7.10 (dd, J=8.4, 2.0 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 4.78 (s,4H), 4.05 (t, J=5.7 Hz, 2H), 2.79 (t, J=5.7 Hz, 2H), 2.37 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.9, 168.9, 155.8, 150.9 (dd, =254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),135.9 (2C), 132.1 (2C), 131.3 (2C), 129.3, 127.2, 127.0 (2C), 126.8,122.8, 118.8 (d, J_(C—CF)=17 Hz, 2C), 117.8 (d, J_(C—CF)=17 Hz, 2C),112.2, 67.5, 57.6, 52.1, 45.9.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(dimethylamino)ethoxy)-2-fluorobenzoyl)piperidin-4-one(JC084)

¹H NMR (500 MHz, CDCl₃) δ 7.75 (br s, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.18(m, 6H), 7.10 (dd, J=8.4, 2.0 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 4.78 (br.s, 4H), 4.05 (t, J=5.7 Hz, 2H), 2.79 (t, J=5.7 Hz, 2H), 2.37 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.9, 169.0, 151.7 (d, J_(CF)=252 Hz), 150.9(dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 148.6 (d, J_(C—CF)=11 Hz), 136.0 (2C), 132.2 (2C),131.3 (2C), 127.0 (2C), 126.5, 123.7, 119.0 (d, J_(C—CF)=17 Hz, 2C),117.9 (d, J_(C—CF)=17 Hz, 2C), 115.6 (d, J_(C—CF)=20 Hz), 113.8, 67.5,57.8, 56.2, 45.8.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(2-(dimethylamino)ethoxy)benzoyl)piperidin-4-one(JC085)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 1H), 7.59 (s, 1H), 7.34 (m, 1H), 7.22(m, 3H), 7.09 (m, 1H), 7.03 (m, 1H), 6.83 (m, 3H), 6.72 (m, 1H), 5.09(s, 1H), 4.93 (s, 1H), 4.48 (s, 2H), 3.99 (m, 2H), 2.72 (m, 2H), 2.33(s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 168.0, 154.1, 151.0 (dd, =254 Hz,J_(C—CF)=14 Hz), 150.6 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz), 150.4 (dd,J_(CF)=254 Hz, J_(C—CF)=14 Hz), 150.0 (dd, J_(CF)=254 Hz, J_(C—CF)=14Hz), 136.5, 134.6, 132.6, 132.0, 131.5 (dd, J_(C—C—CF)=6.0 Hz,J_(C—C—CF)=4.2 Hz), 131.2 (dd, J_(C—C—CF)=5.2 Hz, J_(C—C—CF)=3.8 Hz),131.0 (2C), 127.8, 127.5 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.9 Hz),126.6 (dd, J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=3.2 Hz), 124.3, 121.3, 119.4(d, J_(C—CF)=17 Hz), 118.3 (d, J_(C—CF)=17 Hz), 117.9 (d, J_(C—CF)=17Hz), 117.6 (d, J_(C—CF)=17 Hz), 66.3, 57.4, 46.9, 45.5, 43.0.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(2-(2-(dimethylamino)ethoxy)benzoyl)piperidin-4-one(JC086)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 2H) 7.15 (m, 6H), 6.99 (m, 1H),6.83 (m, 1H), 6.81 (m, 1H), 6.71 (m, 1H), 4.78 (br s, 4H), 3.93 (t,J=5.7 Hz, 2H), 2.68 (t, J=5.7 Hz, 2H), 2.31 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.0, 170.2, 158.7, 151.0 (dd, J_(CF)=254Hz, J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),136.5 (2C), 135.3, 132.1 (2C), 131.3 (2C), 129.3, 126.8 (2C), 119.0,118.7 (d, J_(C—CF)=18 Hz, 2C), 117.8 (d, J_(C—CF)=17 Hz, 2C), 116.3,113.2, 66.1, 65.6, 58.0, 57.9, 45.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-((dimethylamino)methyl)benzoyl)piperidin-4-one(JC087)

¹H NMR (400 MHz, (CD₃)₂CO)) δ 7.71 (br s, 2H), 7.38 (m, 6H), 7.15 (d,J=5.7 Hz, 2H), 7.08 (d, J=5.7 Hz, 2H), 4.87 (br s, 4H), 3.27 (s, 2H),2.06 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 170.5, 151.0 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),141.5, 136.6 (2C), 132.6, 132.2 (2C), 131.4 (2C), 128.8, 127.0 (2C),126.8, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.9 (d, J_(C—CF)=18 Hz, 2C),63.7, 56.0, 45.0.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)benzamide(JC099)

To a mixture of the tert-butyl (4-oxocyclohexyl)carbamate (213.28 mg, 1mmol, 1.0 equiv) and ethanol (1.0 mL) in a round bottom flask was addeddropwise 20% aqueous sodium hydroxide (1.0 mL) and the reaction mixturewas stirred for 5 min. To this mixture was added3,4-difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv). The reactionmixture was then allowed to stir at 21° C. for 5 h. The yellowprecipitate thus obtained was filtered, washed with water and coldethanol and dried to get the pure product (360 mg, 78% yield).

Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)carbamate (230.7mg, 0.5 mmol) in methylene chloride (5.0 ml) at 21° C. and the mixturewas stirred overnight at 21° C. The reaction solution was distilled offunder reduced pressure and the resulting residue was poured into a1N-aqueous sodium hydroxide solution and extracted with ethyl acetateand chloroform. The organic layer was washed with a saturated aqueoussodium chloride solution and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtain4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

A mixture of4-amino-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one (180.7 mg,0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (70 μL, 0.5 mmol, 1.0equiv.) in dichloromethane was maintained at 0° C. (ice bath). To thiscooled mixture was added dropwise 4-(2-(diethylamino)ethoxy)benzoylchloride (127.9 mg, 0.5 mmol, 1.0 equiv.) in 2.0 mL dichloromethane.After the complete addition of the acid chloride, the reaction mixturewas slowly warmed up to 21° C. and stirred overnight. The reactionsolvent was evaporated under reduced pressure and the residue wasstirred with satd. aqueous K₂CO₃ for 4 h. The mixture was extractedthree times with ethyl acetate and dichloromethane. The organic layerwas washed with a satd. aqueous sodium chloride solution and then driedover anhydrous sodium sulfate. The solvent was evaporated, followed byflash chromatography on silica gel (gradient elution 10%methanol/EtOAc-15% methanol/EtOAc) to give the desired compound JC099(250 mg, 86% yield) as a yellow solid.

Synthesis of 4-(2-(diethylamino)ethoxy)benzoyl chloride Method 2 Methyl4-hydroxybenzoate (5.0 g, 32.86 mmol, 10. equiv) was combined with1,2-dibromoethane (35 mL) and potassium carbonate (6.8 g, 49.23 mmol,1.5 equiv) then the mixture was heated at reflux for 18 h. The reactionmixture was concentrated under reduced pressure and then the residue waspartitioned between ethyl ether (300 mL) and water (200 mL). The etherlayer was extracted with 2 N sodium hydroxide (5×30 mL). The solvent wasremoved to give the desired product as a white solid (8.5 g, 99% yield).

To a round bottom flask equipped with a stir-bar was added a solution ofmethyl 4-(2-bromoethoxy)-benzoate (2.591 g, 10 mmol, 1.0 equiv), DMF (20mL), potassium carbonate (4.146 g, 30 mmol, 3.0 equiv) and diethylamine(3.1 mL, 30 mmol, 3.0 equiv). The mixture was heated at 75° C. for 24 h,after which time EtOAc (200 mL) and water (200 mL) were added. Theorganic layer was washed with water three times and then dried oversodium sulfate. The pure product was obtained by flash chromatography onsilica gel (gradient elution 10% methanol/DCM-15% methanol/DCM) to givethe desired product, methyl 4-(2-(diethylamino)ethoxy)benzoate (1.281 g,51% yield), as a light brown oil.

Methyl 4-(2-(diethylamino)ethoxy)benzoate (1.116 g, 5.0 mmol, 1.0 equiv)was dissolved in 2.5 mL ethanol and added to a solution of sodiumhydroxide (0.4 g) in 2.5 mL water. The mixture was heated under refluxfor 2 h. The ethanol was removed in vacuo and the aqueous solution wasacidified with conc. HCl at 5° C. The solid was collected, treated withcold water, filtered and dried at 55-60° C. in vacuo to give4-(2-(diethylamino)ethoxy)benzoic acid hydrochloride as white sold(1.149 g, 84% yield).

To a stirred mixture of 4-(2-(diethylamino)ethoxy)benzoic acidhydrochloride (273.76 mg, 1.0 mmol) was added thionyl chloride (2.5 mL).The mixture was heated at reflux for 4 h. The thionyl chloride wasremoved in vacuo and the residue dried to give4-(2-(diethylamino)ethoxy)benzoyl chloride which was enough pure to beused for next step.

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 2H), 7.63 (d, J=8.9 Hz, 2H), 7.21 (m,6H), 6.89 (d, J=8.9 Hz, 2H), 6.07 (d, J=7.0 Hz, 1H), 4.50 (m, 1H), 4.14(t, J=5.5 Hz, 2H), 3.26 (bd, J=15.8 Hz, 2H), 3.07 (dd, J=16.4 Hz, J=5.6Hz, 2H), 2.96 (t, J=5.0 Hz, 2H), 2.73 (m, 4H), 1.12 (t, J=7.1 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.9, 166.6, 161.6, 150.7 (dd, =254 Hz,J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz, 2C),137.8 (2C), 132.8 (2C), 132.2 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz,2C), 128.7 (2C), 127.1 (dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=3.5 Hz, 2C),126.3, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.7 (d, J_(C—CF)=18 Hz, 2C),114.4 (2C), 66.5, 51.5, 47.9, 44.6, 33.8, 11.5.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-((2-(dimethylamino)ethyl)thio)benzoyl)piperidin-4-one(JC100)

¹H NMR (500 MHz, CDCl₃) δ 7.74 (br s 2H), 7.23 (m, 6H), 7.13 (d, J=8.3Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 4.78 (br s, 4H), 2.99 (t, J=7.5 Hz,2H), 2.56 (t, J=7.5 Hz, 2H), 2.28 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 170.1, 151.0 (dd, J_(CF)=255 Hz,J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C),140.8, 136.0, 132.2 (2C), 131.9, 131.1 (2C), 130.6 (2C), 127.6, 126.9,122.4, 119.0 (d, J_(C—CF)=18 Hz, 2C), 117.8 (d, J_(C—CF)=18 Hz, 2C),115.2 (2C), 65.6, 58.0, 50.2, 45.2, 30.4.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-((2-(dimethylamino)ethyl)amino)benzoyl)piperidin-4-one(JC102)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.14 (m, 8H), 7.04 (d, J=8.4Hz, 2H), 6.28 (br s, 1H), 4.80 (br s, 4H), 3.26 (t, J=6.2 Hz, 2H), 2.73(t, J=6.2 Hz, 2H), 2.42 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 169.6, 151.1 (dd, J_(CF)=255 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=250 Hz, J_(C—CF)=11 Hz, 2C),145.0, 135.9, 133.2, 132.4, 131.8 (2C), 129.0, 127.3 (dd, J_(C—C—CF)=5.9Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.9 (dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=4.5Hz, 2C), 122.3, 119.2 (d, J_(C—CF)=18 Hz, 2C), 117.9 (d, J_(C—CF)=17 Hz,2C), 109.0 (2C), 65.9, 56.9, 48.8, 44.7, 29.7.

1-(3,4-Bis(2-(dimethylamino)ethoxy)benzoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC103)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.06 (m, 8H), 6.88 (d, J=7.0Hz, 1H), 4.81 (br s, 4H), 3.99 (t, J=5.8 Hz, 4H), 2.73 (t, J=5.8 Hz,4H), 2.35 (br s, 12H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 170.3, 151.0 (dd, J_(CF)=255 Hz,J_(C—CF)=13 Hz, 2C), 150.2 (dd, J_(CF)=254 Hz, J_(C—CF)=13 Hz, 2C),148.5, 135.9, 132.3 (2C), 131.5 (2C), 127.0, 126.4 (2C), 120.3 (2C),119.1 (d, J_(C—CF)=17 Hz, 2C), 117.9 (d, J_(C—CF)=18 Hz, 2C), 113.7(2C), 68.8, 66.7, 57.8, 56.3, 45.6, 30.2.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-(2-(dimethylamino)ethoxy)-4-hydroxybenzoyl)piperidin-4-one(JC104)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 1H), 7.09 (m, 8H), 6.80 (d, J=6.8Hz, 1H), 6.62 (br s 1H), 4.78 (br s, 4H), 3.96 (t, J=5.7 Hz, 2H), 2.63(t, J=5.6 Hz, 2H), 2.40 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.3, 170.5, 150.9 (dd, J_(CF)=254 Hz,J_(C—CF)=12 Hz, 2C), 150.6, 150.4 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz,2C), 148.0, 135.8, 132.4 (2C), 131.5 (2C), 130.2 (2C), 127.1, 126.9,119.1 (d, J_(C—CF)=17 Hz), 118.9 (d, J_(C—CF)=18 Hz), 117.9, 117.6 (d,J_(C—CF)=18 Hz), 117.0 (d, J_(C—CF)=17 Hz), 116.3 (2C), 69.2, 66.8,57.5, 45.5, 29.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(dimethylamino)ethoxy)-3-nitrobenzoyl)piperidin-4-one(JC105)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.67 (s, 1H), 7.08 (m, 8H), 6.62(d, J=7.6 Hz, 1H), 4.96 (s, 2H), 4.50 (s, 2H), 4.16 (t, J=5.6 Hz, 2H),2.78 (t, J=5.6 Hz, 2H), 2.34 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.7, 165.5, 151.2, 151.0 (dd, =250 Hz,J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=255 Hz, J_(C—CF)=11 Hz, 2C),138.3, 137.1, 135.3, 132.2, 131.9 (2C), 131.4 (dd, J_(C—C—CF)=5.9 Hz,J_(C—C—CF)=3.4 Hz, 2C), 130.9, 127.4, 126.4, 119.2 (d, J_(C—CF)=18 Hz),118.9 (d, J_(C—CF)=18 Hz), 118.1 (d, J_(C—CF)=18 Hz), 118.0, 117.9 (d,J_(C—CF)=17 Hz), 115.2, 68.4, 65.2, 57.4, 45.7, 29.9.

1-Acetyl-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (JC106)

¹H NMR (500 MHz, CDCl₃) δ 7.74 (s, 1H), 7.69 (s, 1H), 7.22 (m, 6H), 4.85(s, 2H), 4.67 (s, 2H), 1.96 (s, 3H)

¹³C NMR (126 MHz, CDCl₃) δ 185.9, 169.2, 150.9 (dd, J_(CF)=255 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=11 Hz, 2C),136.4, 135.3, 132.1, 131.6, 127.3 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.4Hz, 2C), 126.8 (dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.5 Hz, 2C), 119.2 (d,J_(C—CF)=18 Hz), 118.9 (d, J_(C—CF)=18 Hz), 118.1 (d, J_(C—CF)=18 Hz),117.9 (d, J_(C—CF)=17 Hz), 46.9, 43.1, 21.1.

1-(3-Chloro-4-(2-(piperidin-1-yl)ethoxy)benzoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC109)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 2H), 7.15 (m, 8H), 6.66 (d, J=8.5 Hz,1H), 4.80 (br s, 4H), 4.09 (t, J=6.0 Hz, 2H), 2.82 (t, J=6.0 Hz, 2H),2.54 (m, 4H), 1.61 (m, 4H), 1.45 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 185.9, 168.9, 155.8, 151.0 (dd, J_(CF)=254Hz, J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz, 2C),132.1 (2C), 131.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.1 Hz, 2C), 129.3(2C), 127.2 (2C), 127.0 (dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.7 Hz, 2C),126.8, 122.8, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.7 (d, J_(C—CF)=18 Hz,2C), 112.2, 67.2, 57.2, 55.0, 25.6, 23.8.

1-(3-Chloro-4-(2-(diethylamino)ethoxy)benzoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC110)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.13 (m, 8H), 6.67 (d, J=8.5Hz, 1H), 4.79 (br s, 4H), 4.14 (t, J=5.6 Hz, 2H), 3.09 (t, J=5.6 Hz,2H), 2.83 (q, J=7.1 Hz, 4H), 1.17 (t, J=7.2 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.9, 168.9, 155.5, 151.0 (dd, J_(CF)=254Hz, J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=251 Hz, J_(C—CF)=13 Hz, 2C),136.2, 132.1 (2C), 131.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz, 2C),129.3 (2C), 127.2 (2C), 127.0 (dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.7 Hz,2C), 122.6, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.7 (d, J_(C—CF)=18 Hz,2C), 112.2, 66.7, 50.9, 47.7, 29.7, 10.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)benzoyl)piperidin-4-one(JC111)

¹H NMR (400 MHz, CDCl₃) δ 7.75 (br s, 2H), 7.16 (m, 6H), 6.96 (m, 2H),6.67 (m, 1H), 4.78 (br s, 4H), 4.10 (t, J=6.0 Hz, 2H), 2.82 (t, J=6.0Hz, 2H), 2.49 (m, 4H), 1.64 (m, 4H), 1.45 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 186.0, 169.1, 151.6 (d, J_(CF)=252 Hz), 151.1(dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=251 Hz,J_(C—CF)=11 Hz, 2C), 148.6 (d, J_(C—C—CF)=11 Hz), 136.1 (2C), 132.2(2C), 131.3 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.9 (dd,J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.4 (d, J_(C—C—CF)=5.5 Hz),123.7 (J_(C—C—CF)=3.4 Hz), 118.4 (d, J_(C—CF)=18 Hz, 2C), 117.9 (d,J_(C—CF)=18 Hz, 2C), 115.5 (d, J_(C—CF)=20 Hz), 113.9, 67.2, 57.4, 55.1,54.9, 25.6, 23.9.

1-(4-(2-(Diethylamino)ethoxy)-3-fluorobenzoyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC112)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (br s, 2H), 7.15 (m, 6H), 6.95 (m, 2H),6.67 (m, 1H), 4.77 (br s, 4H), 4.03 (t, J=6.2 Hz, 2H), 2.91 (t, J=6.2Hz, 2H), 2.66 (q, J=7.2 Hz, 4H), 1.08 (t, J=7.2 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.0, 169.1, 151.7 (d, =250 Hz), 151.0 (dd,J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz,J_(C—CF)=13 Hz, 2C), 148.7 (d, J_(C—C—CF)=11 Hz), 136.1 (2C), 132.2(2C), 131.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.9 (dd,J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.7 Hz, 2C), 126.3 (d, J_(C—C—CF)=5.5 Hz),123.7 (J_(C—C—CF)=3.7 Hz), 118.9 (d, J_(C—CF)=17 Hz, 2C), 117.8 (d,J_(C—CF)=18 Hz, 2C), 115.5 (d, J_(C—CF)=20 Hz), 113.6, 67.7, 51.3, 47.9,11.6.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-chloro-4-(2-(piperidin-1-yl)ethoxy)Benzamide(JC113)

¹H NMR (400 MHz, CDCl₃) δ 7.70 (br s, 2H), 7.68 (d, J=2.2 Hz, 1H), 7.56(dd, J=2.2 Hz, J=8.6 Hz, 1H,) 7.16 (m, 6H), 6.84 (d, J=8.7 Hz, 1H), 6.64(d, J=7.4 Hz, 1H), 4.40 (m, 1H), 4.14 (t, J=5.9 Hz, 2H), 3.23 (bd,J=16.1 Hz, 2H), 3.00 (dd, J=5.6 Hz, J=17.0 Hz, 2H), 2.83 (t, J=5.9 Hz,2H), 2.61 (m, 4H), 1.58 (m, 4H), 1.43 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 165.6, 156.9, 150.7 (dd, J_(CF)=249Hz, J_(C—CF)=11 Hz, 2C), 150.2 (dd, J_(CF)=252 Hz, J_(C—CF)=13 Hz, 2C),137.7 (2C), 132.8 (2C), 132.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.5 Hz,2C), 129.1 (2C), 127.2 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.4 Hz, 2C),122.9, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=17 Hz, 2C),112.3 (2C), 67.4, 57.3, 55.1, 44.9, 33.6, 25.7, 23.9.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-chloro-4-(2-(diethylamino)ethoxy)Benzamide(JC114)

¹H NMR (300 MHz, CDCl₃) δ 7.75 (br s, 2H), 7.70 (d, J=2.2 Hz, 1H), 7.56(dd, J=2.2 Hz, J=8.6 Hz, 1H,) 7.19 (m, 6H), 6.86 (d, J=8.7 Hz, 1H), 6.44(d, J=7.4 Hz, 1H), 4.43 (m, 1H), 4.14 (t, J=5.9 Hz, 2H), 3.25 (bd,J=13.5 Hz, 2H), 3.03 (dd, J=5.6 Hz, J=14.0 Hz, 2H), 2.93 (t, J=5.7 Hz,2H), 2.71 (q, J=7.1 Hz, 4H), 1.09 (t, J=7.2 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 165.6, 156.9, 150.6 (dd, =250 Hz,J_(C—CF)=13 Hz, 2C), 150.1 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz, 2C),137.6 (2C), 132.8 (2C), 132.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.5 Hz,2C), 129.2 (2C), 127.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz, 2C),122.9, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=18 Hz, 2C),112.4 (2C), 67.4, 57.3, 55.1, 44.9, 33.7, 25.7, 23.9.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-fluoro-4-(2-(piperidin-1-yl)ethoxy)benzamide(JC115)

¹H NMR (300 MHz, CDCl₃) δ 7.77 (br s, 2H), 7.49 (m, 2H), 7.22 (m, 6H),6.94 (m, 1H), 6.54 (d, J=7.2 Hz, 1H), 4.47 (m, 1H), 4.21 (t, J=6.0 Hz,2H), 3.28 (bd, J=15.6 Hz, 2H), 3.06 (dd, J=7.0 Hz, J=15.3 Hz, 2H), 2.84(t, J=6.0 Hz, 2H), 2.56 (m, 4H), 1.63 (m, 4H), 1.48 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 165.6, 151.9 (d, J_(CF)=248 Hz), 150.7(dd, J_(CF)=254 Hz, J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=250 Hz,J_(C—CF)=13 Hz, 2C), 149.8 (d, J_(C—C—CF)=11 Hz), 137.7, 132.8 (2C),132.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 127.1 (dd,J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.4 Hz, 2C), 126.7 (d, J_(C—C—CF)=5.5 Hz),123.6 (J_(C—C—CF)=3.3 Hz), 123.6, 118.9 (d, J_(C—CF)=17 Hz, 2C), 117.6(d, J_(C—CF)=18 Hz, 2C), 115.2 (d, J_(C—CF)=20 Hz), 113.9, 67.3, 57.5,55.1, 44.9, 33.7, 25.7, 23.9.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(diethylamino)ethoxy)-3-fluorobenzamide(JC116)

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 2H), 7.40 (m, 2H), 7.24 (m, 6H), 6.94(m, 1H), 5.99 (d, J=7.1 Hz, 1H), 4.50 (m, 1H), 4.13 (t, J=6.2 Hz, 2H),3.26 (bd, J=15.7 Hz, 2H), 3.06 (dd, J=15.8 Hz, J=6.0 Hz, 2H), 2.92 (t,J=6.2 Hz, 2H), 2.65 (q, J=7.0 Hz, 4H), 1.07 J=7.1 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 165.6, 151.9 (d, J_(CF)=248 Hz), 150.6(dd, J_(CF)=254 Hz, J_(C—CF)=13 Hz, 2C), 150.2 (dd, J_(CF)=250 Hz,J_(C—CF)=13 Hz, 2C), 149.8 (d, J_(C—C—CF)=11 Hz), 137.7, 132.7 (2C),132.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 127.1 (dd,J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.4 Hz, 2C), 126.7 (d, J_(C—C—CF)=5.5 Hz),123.6 (J_(C—C—CF)=3.3 Hz), 123.5, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.6(d, J_(C—CF)=18 Hz, 2C), 115.1 (d, J_(C—CF)=20 Hz), 113.7, 67.9, 51.4,47.9, 44.9, 33.7, 11.6.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)ethoxy)-3-fluorobenzamide(JC117)

¹H NMR (300 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.48 (m, 2H), 7.21 (m, 6H),6.94 (m, 1H), 6.55 (d, J=7.2 Hz, 1H), 4.47 (m, 1H), 4.17 (t, J=5.7 Hz,2H), 3.28 (bd, J=15.7 Hz, 2H), 3.06 (dd, J=5.7 Hz, J=15.7 Hz, 2H), 2.81(t, J=5.8 Hz, 2H), 2.38 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 187.8,165.6, 151.8 (d, J_(CF)=248 Hz), 150.6 (dd, J_(CF)=254 Hz, J_(C—CF)=13Hz, 2C), 150.2 (dd, J_(CF)=256 Hz, J_(C—CF)=11 Hz, 2C), 149.7 (d,J_(C—C—CF)=11 Hz), 137.6, 132.7 (2C), 132.1 (dd, J_(C—C—CF)=5.8 Hz,J_(C—C—CF)=4.2 Hz, 2C), 127.1 (dd, J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.4 Hz,2C), 126.7 (d, J_(C—C—CF)=5.5 Hz), 123.6 (J_(C—C—CF)=3.4 Hz), 123.5,118.9 (d, J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=18 Hz, 2C), 115.1 (d,J_(C—CF)=18 Hz), 113.9, 67.5, 57.8, 45.9, 44.9, 33.7.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3-chloro-4-(2(dimethylamino)ethoxy) Benzamide (JC118)

¹H NMR (300 MHz, CDCl₃) δ 7.80 (br s, 2H), 7.75 (d, J=2.2 Hz, 1H), 7.61(dd, J=2.2 Hz, J=8.6 Hz, 1H,) 7.23 (m, 6H), 6.91 (d, J=8.6 Hz, 1H), 6.43(d, J=7.1 Hz, 1H), 4.49 (m, 1H), 4.23 (t, J=5.5 Hz, 2H), 3.30 (bd,J=13.5 Hz, 2H), 3.08 (dd, J=5.6 Hz, J=14.0 Hz, 2H), 2.93 (t, J=5.5 Hz,2H), 2.47 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 165.5, 155.8, 150.6 (dd, J_(CF)=249Hz, J_(C—CF)=13 Hz, 2C), 150.1 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz, 2C),137.8 (2C), 132.8 (2C), 132.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz,2C), 129.2 (2C), 127.2 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.4 Hz, 2C),122.9, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=18 Hz, 2C),112.4 (2C), 67.4, 57.6, 45.9, 44.9, 33.7.

N-(3,5-Bis((E)-4-chloro-3-fluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)ethoxy)benzamide(JC122)

¹H NMR (400 MHz, CDCl₃) δ 7.80 (br s, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.43(app. t, J=7.9 Hz, 2H), 7.22 (d, J=10.0 Hz, 2H), 7.17 (d, 1H, J=8.3 Hz,2H), 6.90 (d, J=8.8 Hz, 2H), 4.49 (m, 1H), 4.13 (t, J=5.5 Hz, 2H), 3.28(m, 2H), 3.06 (m, 2H), 2.83 (t, J=5.5 Hz, 2H), 2.41 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.6, 166.4, 160.0 (d, J_(CF)=249 Hz, 2C),156.8 (2C), 137.6 (2C), 135.4 (d, J_(C—C—CF)=7.0 Hz, 2C), 133.3 (2C),130.7, 128.6, 126.8 (d, J_(C—C—CF) 2C), 126.3, 121.9 (d, J_(C—CF)=17 Hz,2C), 117.8 (d, J_(C—CF)=17 Hz, 2C), 114.3, 57.7, 45.4, 44.4, 33.7, 29.6.

N-(3,5-Bis((E)-4-chloro-3-fluorobenzylidene)-4-oxocyclohexyl)-4-(2-morpholinoethoxy)benzamide (JC123)

¹H NMR (400 MHz, CDCl₃) δ 7.80 (br s, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.42(m, 2H), 7.21 (m, 2H), 7.16 (m, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.49 (m,1H), 4.12 (t, J=5.7 Hz, 2H), 3.72 (m, 4H), 3.26 (m, 2H), 3.06 (m, 2H),2.80 (t, J=5.7 Hz, 2H), 2.56 (m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 187.6, 166.4, 157.0 (d, J_(CF)=252 Hz, 2C),138.2, 137.7, 137.0, 135.4 (d, J_(C—C—CF)=6.9 Hz), 134.3, 133.2, 130.7,129.9 (2C), 128.7, 128.6 (2C), 126.8 (d, J_(C—C—CF)=3.5 Hz), 121.8 (d,J_(C—CF)=18 Hz, 2C), 117.7 (d, J_(C—CF)=18 Hz, 2C), 114.3, 66.6, 57.3,53.9, 44.4, 40.4, 33.7.

N-(3,5-Bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)-4-(2-morpholinoethoxy)benzamide(JC124)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.63 (d, J=8.9 Hz, 2H), 7.35(s, 2H), 7.28 (m, 4H), 6.90 (d, J=8.9 Hz, 2H), 4.52 (m, 1H), 4.13 (t,J=5.7 Hz, 2H), 3.73 (m, 4H), 3.22 (m, 2H), 3.08 (m, 2H), 2.80 (t, J=5.7Hz, 2H), 2.57 (m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 189.9, 188.6, 187.3, 166.4, 138.4, 137.8,137.5, 137.3, 136.6, 136.0, 135.9, 135.1, 134.6, 135.2, 134.4, 134.0,128.9, 128.8, 128.7, 128.6, 128.2, 128.1, 128.0, 127.5, 127.4, 114.4,57.3, 53.8, 40.1, 34.1, 33.6, 29.6.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-morpholinoethoxy)benzamide(JC125)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (br s, 2H), 7.63 (d, J=8.9 Hz, 2H), 7.21(m, 6H), 6.87 (d, J=8.9 Hz, 2H), 4.48 (m, 1H), 4.12 (t, J=5.7 Hz, 2H),3.72 (m, 4H), 3.25 (m, 2H), 3.04 (m, 2H), 2.80 (t, J=5.7 Hz, 2H), 2.57(m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 187.7, 166.4, 151.0 (dd, =248 Hz, J_(C—CF)=13Hz, 2C), 150.4 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C), 137.7, 132.6(2C), 132.0 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.4 Hz, 2C), 131.5 (d,=17 Hz, 2C), 128.6 (2C), 127.0 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8Hz, 2C), 126.2, 118.8 (d, J_(C—CF)=17 Hz, 2C), 117.6 (d, J_(C—CF)=17 Hz,2C), 114.3, 114.1 (d, J_(C—CF)=17 Hz, 2C), 66.7, 65.8, 57.3, 54.0, 44.5,33.6.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-morpholinoethoxy)benzoyl)piperidin-4-one(JC126)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (br s, 2H), 7.15 (m, 8H), 6.62 (d, J=8.8Hz, 2H), 4.78 (br s, 4H), 4.01 (t, J=5.7 Hz, 2H), 3.73 (m, 4H), 2.77 (t,J=5.7 Hz, 2H), 2.55 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 170.2, 160.2, 151.0 (dd, =248 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C),135.6 (2C), 132.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz, 2C), 131.3(2C), 128.9, 126.9 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.4 Hz, 2C),126.0, 118.9 (d, J_(C—CF)=17 Hz, 2C), 117.8 (d, J_(C—CF)=17 Hz, 2C),113.9, 66.7, 65.7, 57.3, 53.9, 53.4.

N-(3,5-Bis((E)-2-chloro-3-(trifluoromethyl)benzylidene)-4-oxocyclohexyl)-4-(2(dimethylamino)ethoxy)benzamide (JC127)

¹H NMR (400 MHz, CDCl₃) δ 8.00 (br s, 2H), 7.67 (m, 2H), 7.57 (d, J=8.9Hz, 2H), 7.40 (m, 4H), 6.88 (d, J=8.9 Hz, 2H), 4.46 (m, 1H), 4.08 (t,J=7.0 Hz, 2H), 3.00 (m, 4H), 2.74 (t, J=5.6 Hz, 2H), 2.34 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.6, 170.3, 161.5, 135.4 (2C), 135.2,134.9, 134.2, 133.9 (2C), 133.3 (2C), 132.8, 132.7, 130.0 (q,J_(C—CF)=38 Hz), 129.4 (q, J_(C—CF)=38 Hz), 128.4, 128.1, 128.0, 126.8(2C), 122.6 (q, J_(CF)=272 Hz, 2C), 114.3, 65.8, 57.9, 45.7, 44.3, 33.6.

N-(3,5-Bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)ethoxy)benzamide(JC128)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (br s, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.34(s, 2H), 7.24 (s, 4H), 6.90 (d, J=8.8 Hz, 2H), 4.51 (m, 1H), 4.09 (t,J=5.6 Hz, 2H), 3.21 (m, 2H), 3.06 (m, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.35(s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 187.4, 166.4, 161.5, 137.8 (2C), 137.3 (2C),135.2, 134.0 (2C), 128.9 (2C), 128.7 (2C), 128.0, 126.2 (2C), 114.3,65.8, 57.9, 45.7, 44.3, 33.6.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(dimethylamino)ethoxy)-2-fluorobenzoyl)piperidin-4-one(JC131)

¹H NMR (400 MHz, CDCl₃) δ 7.68 (hr s, 2H), 7.09 (br m, 7H), 6.56 (dd,J=8.6, 2.3 Hz, 1H), 6.41 (dd, J=11.6, 2.3 Hz, 1H), 5.01 (br m, 2H), 4.54(br m, 2H), 3.98 (t, J=5.6 Hz, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.35 (s,6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.6, 165.6, 161.4 (d, J_(C—CF)=10 Hz),158.9 (d, J_(CF)=252 Hz), 151.0 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C),150.4 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C), 136.6 (2C), 134.9 (2C),131.3, 129.8, 127.3 (2C), 126.3 (2C), 118.7 (d, J_(C—CF)=18 Hz, 2C),117.4 (d, J_(C—CF)=18 Hz, 2C), 110.8, 101.7 (d, J_(C—CF)=20 Hz), 66.1,57.6, 46.9, 45.5, 43.5.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(dimethylamino)ethoxy)-3-(trifluoromethyl)Benzoyl)piperidin-4-one (JC132)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (br s, 2H), 7.44 (m, 2H), 7.11 (m, 6H),6.76 (d, J=8.6 Hz, 1H), 4.81 (br s, 4H), 4.11 (t, J=5.7 Hz, 2H), 2.79(t, J=5.7 Hz, 2H), 2.35 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 185.8, 169.0, 158.1, 151.0 (dd, J_(CF)=255Hz, J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C),136.1 (2C), 132.9 (2C), 131.9 (2C), 131.2, 126.9 (2C), 126.5, 126.4,125.6, 122.7 (q, J_(CF)=272 Hz), 119.0 (d, J_(C—CF)=18 Hz), 118.9 (d,J_(C—CF)=18 Hz), 117.8 (d, J_(C—CF)=18 Hz, 2C), 112.3, 67.8, 57.5, 45.9,29.7.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)ethoxy)-2-fluorobenzamide(JC133)

¹H NMR (400 MHz, CDCl₃) δ 7.96 (m, 1H), 7.81 (br s, 2H), 7.20 (m, 6H),6.76 (dd, J=8.9, 2.4 Hz, 1H), 6.71 (m, 1H), 6.61 (dd, J=8.8, 2.3 Hz,1H), 4.54 (m, 1H), 4.15 (t, J=5.4 Hz, 2H), 3.23 (bd, J=15.7 Hz, 2H),3.09 (dd, J=15.7, 7.0 Hz, 2H), 2.85 (t, J=5.3 Hz, 2H), 2.42 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 189.8, 187.9, 162.6, 161.5 (d, J_(CF)=247Hz), 150.7 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C), 150.2 (dd,J_(CF)=251 Hz, J_(C—CF)=13 Hz, 2C), 138.3, 137.9, 137.4, 134.8, 133.9,133.3, 133.2, 132.7, 132.2 (2C), 127.0 (dd, J_(C—C—CF)=6.2 Hz,J_(C—C—CF)=3.2 Hz), 126.3 (dd, J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.7 Hz),118.9 (d, J_(C—CF)=18 Hz), 118.5 (d, J_(C—CF)=19 Hz), 117.6 (d,J_(C—CF)=19 Hz), 116.7 (d, J_(C—CF)=17 Hz), 113.1 (d, J_(C—CF)=11 Hz),111.3, 111.2, 102.4, 102.1, 65.9, 57.6, 45.1, 44.6, 40.4, 34.2, 33.6.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(2-(dimethylamino)ethoxy)-3-(trifluoromethyl)benzamide(JC134)

¹H NMR (400 MHz, CDCl₃) δ 7.88 (m, 1H), 7.72 (br s, 2H), 7.16 (m, 7H),6.95 (d, J=8.7 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H), 4.45 (m, 1H), 4.18 (t,J=5.6 Hz, 2H), 3.26 (bd, J=15.9 Hz, 2H), 3.03 (dd, J=15.8 Hz, J=5.8 Hz,2H), 2.81 (t, J=5.6 Hz, 2H), 2.35 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.8, 165.5, 159.1, 150.7 (dd, J_(CF)=255Hz, J_(C—CF)=11 Hz, 2C), 150.1 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C),137.7 (2C), 134.5, 132.8 (2C), 132.7 (2C), 132.1 (dd, J_(C—C—CF)=5.7 Hz,J_(C—C—CF)=3.5 Hz, 2C), 129.2 (q, J_(C—CF)=38 Hz), 127.1 (dd,J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 125.8, 122.6 (q, =272 Hz),118.8 (d, J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=18 Hz, 2C), 112.5,67.8, 57.5, 45.8, 45.0, 33.6.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-3,5-dichloro-4-(2-(dimethylamino)ethoxy)benzamide(JC135)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.62 (s, 2H), 7.18 (m, 6H),6.61 (d, J=7.2 Hz, 1H), 4.42 (m, 1H), 4.11 (t, J=5.7 Hz, 2H), 3.26 (bd,J=16.1 Hz, 2H), 3.03 (dd, J=15.9 Hz, J=5.8 Hz, 2H), 2.84 (t, J=5.7 Hz,2H), 2.40 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.6, 164.4, 154.2, 150.7 (dd, J_(CF)=255Hz, J_(C—CF)=13 Hz, 2C), 150.2 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C),137.9 (2C), 132.6 (2C), 132.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz,2C), 131.1, 129.8, 127.8, 127.2 (dd, J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=4.2Hz, 2C), 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.7 (d, J_(C—CF)=18 Hz, 2C),70.9, 58.6, 45.5, 45.2, 33.6.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(prop-2-yn-1-yloxy)benzamide(JC144)

¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J=6.5 Hz, 1H), 7.80 (s, 1H), 7.78(s, 1H), 7.60 (m, 4H), 7.47 (m, 2H), 7.37 (m, 2H), 7.00 (d, J=8.9 Hz,2H), 4.83 (s, 2H), 4.82 (s, 2H), 4.06 (m, 1H), 3.31 (s, 1H), 3.15 (bd,J=15.8 Hz, 2H), 2.98 (dd, J=15.8 Hz, J=5.6 Hz, 2H).

¹³C NMR (126 MHz, DMSO-d₆) δ 188.0, 166.1, 159.9, 150.1 (dd, J_(CF)=248Hz, J_(C—CF)=12 Hz, 2C), 149.7 (dd, J_(CF)=244 Hz, J_(C—CF)=13 Hz, 2C),135.7, 135.1 (2C), 133.2 (dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=3.9 Hz, 2C),129.6, 128.0 (dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=3.1 Hz, 2C), 127.6,119.6 (d, J_(C—CF)=17 Hz, 2C), 118.2 (d, J_(C—CF)=17 Hz, 2C), 114.8(2C), 79.3, 78.9, 56.0, 45.5, 45.4, 33.5.

General Procedure E:

The compounds were generally prepared by reaction of the3,4-difluorobenzaldehyde, with piperidin-4-one hydrogen chloride in thepresent of 40% aq. sodium hydroxide to give3,5-Bis((E)-3,4-difluorobenzylidene)piperidin-4-one, Acylation of3,5-Bis((E)-3,4-difluorobenzylidene)piperidin-4-one with2-chloroethanesulfonyl chloride under base condition afforded the3,5-bis((E)-3,4-difluorobenzylidene)-1-(vinylsulfonyl)piperidin-4-one.Michael addition with amine afforded3,5-bis((E)-3,4-difluorobenzylidene)-1-((2-(dimethylamino)ethyl)sulfonyl)piperidin-4-one

Example JC060

To the mixture of the piperidin-4-one hydrogen chloride (135.59 mg, 1mmol, 1.0 equiv.) and methanol (2.0 mL) in a round bottom flask addeddrop-wise 40% aqueous sodium hydroxide (1.0 mL) and stirred for fiveminutes. To this mixture was added 3,4-difluorobenzaldehyde (355.3 mg,2.5 mmol, 2.5 equiv.). The reaction mixture was then allowed to stir atroom temperature for 3 h. After 3 h the yellow precipitate thus obtainedwas filtered, washed with water, cold methanol and dried to get pureproduct (285 mg, 80% yield).

The mixture of 3,5-Bis((E)-3,4-difluorobenzylidene)piperidin-4-one(173.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (210 μL,1.5 mmol, 3.0 equiv.) in dry dichloromethane was maintained at 0° C.(ice bath). After stir at 0° C. for 20 minutes, to this cooled mixture,2-chloroethanesulfonyl chloride (63 μL, 0.6 mmol, 1.2 equiv.) was addeddrop wise cautiously (exothermic). The reaction mixture was stirred foran addition 20 minutes before being warmed to room temperature andstirred for 4 hours. After such time, the reaction was quenched with 10%aq. HCl (2 mL). The organic layer was separated and washed with water(10 mL) and brine (10 mL). The combined organic solvent was dried overNa₂SO₄, filtered and concentrated under pressure. The crude product3,5-bis((E)-3,4-difluorobenzylidene)-1-(vinylsulfonyl)piperidin-4-onewas pure enough to be used for the next step.

Into a round bottom flask was added crude3,5-bis((E)-3,4-difluorobenzylidene)-1-(vinylsulfonyl)piperidin-4-one(218.7 mg, 0.5 mmol, 1.0 equiv.), dry MeOH (0.5 mL, 1M), dimethylamine(2N in THF) (0.25 mL, 0.5 mmol, 1.0 equiv.) and DBU (7.5 μL, 0.05 mmol,0.1 equiv.) under Ar. The reaction was stirred for 16 hour at roomtemperature, after which the crude reaction mixture was concentrated,followed by flash chromatography (gradient elution 50% DCM/EtOAc) togive yellow solid, dried the solvent by vacuum and added dry DCM (20mL), filtered by cotton to get compound JC060 (139.9 mg, 58% yield).

The following compounds were synthesized by procedure E: JC060, JC088,JC094, JC098, JC107, JC108, JC121.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-((2-(dimethylamino)ethyl)sulfonyl)piperidin-4-one(JC060)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.30 (m, 6H), 4.65 (br s,4H), 3.06 (t, J=6.8 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 2.15 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 184.7, 151.1 (dd, =252 Hz, J_(C—CF)=13 Hz,2C), 150.5 (dd, J_(CF)=249 Hz, J_(C—CF)=13 Hz, 2C), 136.1 (2C), 131.4(2C), 131.3 (dd, J_(C—C—CF)=5.7 Hz, J_(C—C—CF)=4.0 Hz, 2C), 127.1 (dd,J_(C—C—CF)=6.5 Hz, J_(C—C—CF)=3.5 Hz, 2C), 119.0 (d, J_(C—CF)=18 Hz,2C), 118.2 (d, J_(C—CF)=17 Hz, 2C), 53.1, 50.7, 46.5, 45.1, 30.6.

HR-APCI m/z calcd for C₂₃H₂₂F₄N₂O₃S [M+H]=483.13655, found 483.13541.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-2-(dimethylamino)ethane-1-sulfonamide(JC088)

¹H NMR (400 MHz, CDCl₃) δ 7.81 (br s, 2H), 7.21 (m, 6H), 3.99 (m, 1H),3.13 (m, 4H), 3.00 (t, J=6.0 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.07 (s,6H).

¹³C NMR (100 MHz, DMSO-d₆) δ 187.5, 151.0 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),135.9 (2C), 134.5 (2C), 133.2 (dd, J_(C—C—CF)=5.7 Hz, J_(C—C—CF)=4.0 Hz,2C), 128.1 (dd, J_(C—C—CF)=5.7 Hz, J_(C—C—CF)=4.0 Hz, 2C), 119.5 (d,J_(C—CF)=20 Hz, 2C), 118.3 (d, J_(C—CF)=18 Hz, 2C), 53.4, 49.7, 47.9,45.1, 34.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-((2-methoxyethyl)sulfonyl)piperidin-4-one(JC094)

To a mixture of the piperidin-4-one hydrochloride (135.59 mg, 1 mmol,1.0 equiv.) and methanol (2.0 mL) in a round bottom flask added dropwise40% aqueous sodium hydroxide (1.0 mL) and the reaction mixture wasstirred for 5 min. To this mixture was added 3,4-difluorobenzaldehyde(355.3 mg, 2.5 mmol, 2.5 equiv). The reaction mixture was then allowedto stir at 21° C. for 3 h. The yellow precipitate thus obtained wasfiltered, washed with water and cold methanol and dried to get the purepiperidone product (285 mg, 80% yield).

A mixture of 3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (173.7mg, 0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (105 μL, 0.75mmol, 1.5 equiv.) in dichloromethane was maintained at 0° C. (ice bath).To this cooled mixture was added dropwise 2-methoxyethane-1-sulfonylchloride (95.16 mg, 0.6 mmol, 1.2 equiv). After the addition wascomplete, the reaction mixture was slowly warmed up to 21° C. and it wasstirred for a further 4 h. The reaction solvent was evaporated and theresidue thus obtained was washed with water, filtered and dried. Thecrude product was purified by flash chromatography on silica gel(gradient elution 20% EtOAc/Hexane-50% EtOAc/Hexane) to give the desiredcompound JC094 (209 mg, 89%) as a light yellow powder.

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.19 (m, 6H), 4.62 (br s,4H), 3.71 (t, J=5.5 Hz, 2H), 3.29 (s, 3H), 3.21 (t, J=5.5 Hz, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 185.0, 151.1 (dd, J_(CF)=255 Hz, J_(C—CF)=13Hz, 2C), 150.4 (dd, J_(CF)=250 Hz, J_(C—CF)=13 Hz, 2C), 135.8 (2C),131.5 (2C), 131.3 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=4.2 Hz, 2C), 127.1(dd, J_(C—C—CF)=6.6 Hz, J_(C—C—CF)=3.5 Hz, 2C), 119.1 (d, J_(C—CF)=18Hz, 2C), 118.0 (d, J_(C—CF)=18 Hz, 2C), 66.3, 58.7, 56.3, 52.6, 46.6.

HR-APCI m/z calcd for C₂₂H₁₉F₄NO₄S [M+H]=470.10492, found 470.11597.

1-((2-(Diethylamino)ethyl)sulfonyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC098)

¹H NMR (400 MHz, CDCl₃) δ 7.75 (br s, 2H), 7.18 (m, 6H), 4.62 (br s,4H), 3.04 (t, J=6.5 Hz, 2H), 2.83 (t, J=6.5 Hz, 2H), 2.45 (q, J=7.1 Hz,4H), 0.95 (t, J=7.2 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 184.8, 151.0 (dd, =254 Hz, J_(C—CF)=13 Hz,2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=13 Hz, 2C), 136.4 (2C), 131.2(2C), 131.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz, 2C), 127.1 (dd,J_(C—C—CF)=6.7 Hz, J_(C—C—CF)=3.7 Hz, 2C), 119.1 (d, J_(C—CF)=18 Hz,2C), 118.1 (d, J_(C—CF)=18 Hz, 2C), 50.0, 46.8, 46.6, 46.5, 29.7, 11.6.

1-((2-(Bis(2-methoxyethyl)amino)ethyl)sulfonyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC107)

¹H NMR (400 MHz, CDCl₃) δ 7.77 (br s, 2H), 7.20 (m, 6H), 4.63 (br s,4H), 3.40 (t, J=5.5 Hz, 4H), 3.28 (s, 6H), 3.14 (dd, J=5.3 Hz, J=9.6 Hz,2H), 3.01 (dd, J=5.0 Hz, J=9.2 Hz, 2H), 2.69 (t, J=5.5 Hz, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 184.9, 151.2 (dd, J_(CF)=250 Hz, J_(C—CF)=13Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=11 Hz, 2C), 136.4 (2C),131.2 (2C), 131.3 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.9 Hz, 2C), 127.1(dd, J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.8 Hz, 2C), 119.2 (d, J_(C—CF)=18Hz, 2C), 118.1 (d, J_(C—CF)=17 Hz, 2C), 70.7, 58.8, 53.9, 49.5, 48.7,46.6.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-((2-morpholinoethyl)sulfonyl)piperidin-4-one(JC108)

¹H NMR (400 MHz, CDCl₃) δ 7.78 (br s, 2H), 7.19 (m, 6H), 4.66 (br s,4H), 3.63 (m, 4H), 3.08 (t, J=6.8 Hz, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.39(m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 184.8, 151.1 (dd, =255 Hz, J_(C—CF)=13 Hz,2C), 150.5 (dd, J_(CF)=251 Hz, J_(C—CF)=13 Hz, 2C), 136.6 (2C), 131.4(2C), 131.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.8 Hz, 2C), 127.1 (dd,J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.5 Hz, 2C), 119.0 (d, J_(C—CF)=18 Hz,2C), 118.2 (d, J_(C—CF)=17 Hz, 2C), 66.5, 56.0, 53.4, 52.1, 46.7, 29.7.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-2-methoxyethane-1-sulfonamide(JC121)

¹H NMR (400 MHz, CDCl₃) δ 7.58 (br s, 2H), 7.45 (m, 6H), 3.60 (m, 1H),3.53 (t, J=6.0 Hz, 4H), 3.23 (t, J=6.0 Hz, 4H), 3.13 (m, 2H), 3.06 (s,3H), 2.91 (m, 2H).

¹³C NMR (100 MHz, CDCl₃) δ 187.4, 151.0 (dd, J_(CF)=248 Hz, J_(C—CF)=13Hz, 2C), 150.4 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C), 135.9 (2C),134.4 (2C), 133.2 (2C), 128.1 (2C), 119.5 (d, J_(C—CF)=17 Hz, 2C), 118.3(d, J_(C—CF)=17 Hz, 2C), 66.5, 58.2, 51.7, 48.0, 34.7.

General Procedure F: The compounds were generally prepared by reactionof the 3,4-difluorobenzaldehyde, with 4-oxocyclohexane-1-carboxylic acidin the present of 20% aq. sodium hydroxide (1.5 mL) to give3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexane-1-carboxylic acid.3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexane-1-carboxylic acidcoupling with amine afforded3,5-bis((E)-3,4-difluorobenzylidene)-N-(2-(dimethylamino)ethyl)-4-oxocycloexane-1-carboxamide.

Example JC136

To the mixture of the 4-oxocyclohexane-1-carboxylic acid (142.15 mg, 1mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round bottom flask addeddrop-wise 20% aqueous sodium hydroxide (1.0 mL) and stirred for fiveminutes. To this mixture was added 3,4-difluorobenzaldehyde (355.3 mg,2.5 mmol, 2.5 equiv.). The reaction mixture was then allowed to stir atroom temperature for 3 h. After such time, remove MeOH under vacuum,added 1 N HCl (1 mL), the yellow precipitate thus obtained was filtered,washed with water and cold methanol, dried to get pure product (273 mg,70% yield).

To mixture of crude3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexane-1-carboxylic acid(195.2 mg, 0.5 mmol, 1.0 equiv.), N¹,N¹-dimethylethane-1,2-diamine (65.5μL, 0.6 mmol, 1.2 equiv.),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (143.8 mg,0.75 mmol, 1.5 equiv.), hydroxybenzotriazole (101.3 mg, 0.75 mmol, 1.5equiv.) in 1.0 mL anhydrous dichloromethane (2.0 mL) drop wiseN,N-diisopropylethylamine (135 μL, 0.775 mmol, 1.55 equiv.) at roomtemperature. The mixture was stirred for 16 h. The reaction mixture wasdilued with DCM (10 mL) then washed with sat. NaHCO₃ (2×10 mL), water(2×10 mL), brine the dried over Na₂SO₄, filtered. The solvent wasevaporated, followed by flash chromatography (gradient elution 20%methanol/EtOAC-25% methanol/EtOAC) to give yellow solid, dried thesolvent by vacuum and added dry DCM (10 mL), filtered by cotton to getcompound JC136 (188.8 mg, 82% yield).

The following compounds were synthesized by procedure F: JC136, JC137,JC138, JC139, JC143.

3,5-Bis((E)-3,4-difluorobenzylidene)-N-(2-(dimethylamino)ethyl)-4-oxocyclohexane-1-carboxamide(JC136)

¹H NMR (400 MHz, CDCl₃) δ 7.69 (br s, 2H), 7.24 (m, 2H), 7.15 (m, 4H),6.32 (t, J=4.4 Hz, 1H), 3.33 (m, 2H), 3.05 (m, 4H), 2.46 (m, 1H), 2.40(t, J=5.8 Hz, 2H), 2.15 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 188.8, 173.3, 150.6 (dd, =251 Hz, J_(C—CF)=13Hz, 2C), 150.1 (dd, J_(CF)=248 Hz, J_(C—CF)=14 Hz, 2C), 136.2 (2C),134.1 (2C), 132.4 (dd, J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.1 Hz, 2C), 127.1(dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.2 Hz, 2C), 118.9 (d, J_(C—CF)=18Hz, 2C), 117.5 (d, J_(C—CF)=18 Hz, 2C), 57.5, 45.0, 41.3, 36.8, 31.3.

3,5-Bis((E)-3,5-dichlorobenzylidene)-N-(2-(dimethylamino)ethyl)-4-oxocyclohexane-1-carboxamide(JC137)

¹H NMR (400 MHz, CDCl₃) δ 7.60 (br s, 2H), 7.27 (m, 2H), 7.22 (m, 4H),6.47 (t, J=4.7 Hz, 1H), 3.30 (m, 2H), 3.01 (m, 4H), 2.48 (m, 1H), 2.40(t, J=5.8 Hz, 2H), 2.17 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.4, 173.0, 138.2 (2C), 135.5 (2C), 135.4(2C), 135.1 (2C), 128.7 (2C), 128.2 (2C), 57.5, 44.9, 40.9, 36.7, 31.2.

3,5-Bis((E)-3,5-dichlorobenzylidene)-N-(4-(2-(dimethylamino)ethoxy)phenyl)-4-oxocyclohexane-1-carboxamide(JC138)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 2H), 7.49 (s, 1H), 7.37 (d, J=9.0Hz, 2H), 7.20 (m, 6H), 6.87 (d, J=9.0 Hz, 2H), 4.05 (t, J=5.7 Hz, 2H),3.15 (m, 2H), 2.98 (m, 2H), 2.74 (t, J=5.6 Hz, 2H), 2.58 (m, 1H), 2.35(s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.6, 171.2, 155.6, 138.0 (2C), 135.9 (2C),135.3 (2C), 135.2 (2C), 130.9, 128.9 (2C), 128.2 (2C), 121.8, 114.9,65.7, 57.8, 45.4, 41.8, 31.2.

3,5-Bis((E)-3,4-difluorobenzylidene)-N-(4-(2-(dimethylamino)ethoxy)phenyl)-4-oxocyclohexane-1-carboxamide(JC139)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.43 (s, 1H), 7.41 (d, J=9.0Hz, 2H), 7.21 (m, 6H), 6.85 (d, J=9.0 Hz, 2H), 4.06 (t, J=5.6 Hz, 2H),3.35 (m, 2H), 3.17 (m, 2H), 2.79 (t, J=5.6 Hz, 2H), 2.55 (m, 1H), 2.37(s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 188.8, 171.1, 155.6, 150.9 (dd, =255 Hz,J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C),136.4 (2C), 134.8, 133.7 (2C), 132.1 (dd, J_(C—C—CF)=5.9 Hz,J_(C—C—CF)=3.8 Hz, 2C), 126.9 (dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=4.2 Hz,2C), 121.5, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.5 (d, J_(C—CF)=18 Hz,2C), 114.8, 65.7, 57.8, 45.3, 42.3, 31.3.

3,5-Bis((E)-3,4-difluorobenzylidene)-N-(4-(2-morpholinoethoxy)phenyl)-4-oxocyclohexane-1-carboxamide(JC143)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.68 (br s 2H), 7.42 (d, J=9.0Hz, 2H), 7.15 (m, 6H), 6.83 (d, J=9.0 Hz, 2H), 4.07 (t, J=5.7 Hz, 2H),3.71 (m, 4H), 3.11 (m, 4H), 2.94 (m, 1H), 2.78 (t, J=5.7 Hz, 2H), 2.61(m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 188.1, 171.3, 155.6, 150.7 (dd, J_(CF)=252Hz, J_(C—CF)=13 Hz, 2C), 150.1 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C),136.6, 133.4 (2C), 132.1 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=4.2 Hz, 2C),130.9, 127.1 (dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.6 Hz, 2C), 121.6,119.1 (d, J_(C—CF)=18 Hz, 2C), 117.6 (d, J_(C—CF)=18 Hz, 2C), 115.0(2C), 66.8, 66.0, 57.6, 54.1, 42.2, 31.4.

General Procedure G:

The compounds were generally prepared by reaction of the3,4-difluorobenzaldehyde, with tert-butyl(4-(4-oxocyclohexyl)phenyl)carbamate in the present of 20% aq. sodiumhydroxide to give tert-butyl(4-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)phenyl)-carbamate.TFA deprotected Boc group. Acylation of4-(4-aminophenyl)-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-onewith 3-(dimethylamino)propanoyl chloride under basic conditions affordedtheN-(4-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)phenyl)-3-(dimethylamino)-propanamide

Example JC140

To a solution of 4-(4-nitrophenyl)cyclohexanone (892 mg, 4.07 mmol, 1.0equiv.) in Ethanol (16 mL) at 60° C. was added a solution of ammoniumchloride (2.18 g, 40.7 mmol, 10.0 equiv.) in water (5.0 mL) followed byIron powder (682 mg, 12.2 mmol, 3.0 equiv.) portion wise. The reactionmixture was refluxed for 3 h, cooling to room temperature, filtered andexacted with EtOAc (2×10 mL). The combined organic layers were washedwith brine and dried over MgSO₄, removal of the solvent followed byflash chromatography (gradient elution 25% EtOAC/DCM) to give lightyellow solid (385.1 mg, 50% yield).

To a solution of 4-(4-aminophenyl)cyclohexan-1-one (378.5 mg, 2 mmol,1.0 equiv.) in THF (3.0 mL) cooled in an ice bath was added (Boc)₂O(436.5 mg, 2 mmol, 1.0 equiv.) followed by diisopropylethylamine (348.4μL, 2 mmol, 1.0 equiv.). The mixture was stirred at room temperature for20 h and concentrated. The residue was taken up in ethyl acetate, washedwith brine, dried over Na₂SO₄ and concentrated to get product which isenough pure to be used for next step.

To the mixture of tert-butyl (4-(4-oxocyclohexyl)phenyl)carbamate(289.38 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round bottomflask added drop-wise 20% aqueous sodium hydroxide (1.5 mL) and stirredfor five minutes. To this mixture was added 3,4-difluorobenzaldehyde(355.3 mg, 2.5 mmol, 2.5 equiv.). The reaction mixture was then allowedto stir at room temperature for 5 h. After 5 h the yellow precipitatethus obtained was filtered, washed with water, cold ethanol and dried toget pure product (430 mg, 80% yield).

Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl(4-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)phenyl)carbamate(268.8 mg, 0.5 mmol) in methylene chloride (5.0 ml) at room temperatureand stirred for 3 h at room temperature. Then, the solvent of thereaction solution was distilled off under reduced pressure and theresulting residue was poured into a 1N-aqueous sodium hydroxide solutionand extracted with ethyl acetate and chloroform. The organic layer waswashed with a saturated aqueous sodium chloride solution and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure to obtain4-(4-aminophenyl)-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one.

The mixture of4-(4-aminophenyl)-2,6-bis((E)-3,4-difluorobenzylidene)cyclohexan-1-one(218.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (70 μL, 0.5mmol, 1.0 equiv.) in dichloromethane was maintained at 0° C. (ice bath).To this cooled mixture, 3-(dimethylamino)propanoyl chloride (67.8 mg,0.5 mmol, 1.0 equiv.) in 2.0 mL dichloromethane was added drop wise.After the complete addition of 3-(dimethylamino)propanoyl chloride thereaction mixture was slowly warmed up to room temperature and stirredover night. The mixture was extracted with ethyl acetate anddichloromethane three times. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydroussodium sulfate. The solvent was evaporated, followed by flashchromatography (gradient elution 25% methanol/EtOAC-30% methanol/EtOAC)to give yellow solid, dried the solvent by vacuum and added dry DCM (10mL), filtered by cotton to get compound JC140 (169 mg, 63% yield).

The following compounds were synthesized by procedure G: JC140, JC141.

N-(4-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)phenyl)-3-(dimethylamino)propanamide (JC140)

¹H NMR (400 MHz, CDCl₃) δ 10.9 (s, 1H), 7.73 (br s, 2H), 7.49 (d, J=8.5Hz, 2H), 7.22 (m, 4H), 7.16 (m, 4H), 3.20 (m, 2H), 2.94 (m, 3H), 2.68(t, J=5.6 Hz, 2H), 2.52 (t, J=5.6 Hz, 2H), 2.38 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 188.7, 170.5, 150.9 (dd, =255 Hz, J_(C—CF)=13Hz, 2C), 150.2 (dd, J_(CF)=255 Hz, J_(C—CF)=13 Hz, 2C), 139.1, 137.5(2C), 135.6, 135.3 (2C), 132.4 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.3Hz, 2C), 127.0, 126.9 (dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=3.5 Hz, 2C),120.3, 118.9 (d, J_(C—CF)=18 Hz, 2C), 117.4 (d, J_(C—CF)=18 Hz, 2C),55.0, 44.3, 39.8, 35.7, 33.3.

N-(4-(3,5-Bis((E)-3,5-dichlorobenzylidene)-4-oxocyclohexyl)phenyl)-3-(dimethylamino)-Propanamide(JC141)

¹H NMR (400 MHz, CDCl₃) δ 10.9 (s, 1H), 7.68 (br m, 2H), 7.29 (m, 10H),2.67 (m, 2H), 2.53 (m, 2H), 2.37 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 188.3, 170.3, 138.7, 138.2, 135.4 (2C), 135.2(2C), 135.0 (2C), 128.6, 128.5, 128.1, 128.0, 127.3, 127.0, 120.3 (2C),54.9, 44.3, 39.6, 35.4, 33.2, 29.6.

General Procedure H:

The compounds were generally prepared by reaction of the3,4-difluorobenzaldehyde, with piperidin-4-one hydrogen chloride in thepresent of 40% aq. sodium hydroxide to give3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one, Acylation oralkylation of 3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one withchloride under base condition afforded the 1-acryloyl3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one or 1-alkyl3,5-bis((E)-3,4-difluorobenzyl-idene)piperidin-4-one.

Example JC071

To the mixture of the piperidin-4-one hydrogen chloride (135.59 mg, 1mmol, 1.0 equiv.) and methanol (2.0 mL) in a round bottom flask addeddrop-wise 40% aqueous sodium hydroxide (1.0 mL) and stirred for fiveminutes. To this mixture was added 3,4-difluorobenzaldehyde (355.3 mg,2.5 mmol, 2.5 equiv.). The reaction mixture was then allowed to stir atroom temperature for 3 h. After 3 h the yellow precipitate thus obtainedwas filtered, washed with water, cold methanol and dried to get pureproduct (285 mg, 80% yield).

The mixture of 3,5-Bis((E)-3,4-difluorobenzylidene)piperidin-4-one(173.7 mg, 0.5 mmol, 1.0 equiv.) and anhydrous triethylamine (105 μL,0.75 mmol, 1.5 equiv.) in dichloromethane was maintained at 0° C. (icebath). To this cooled mixture, 4-(dimethylamino)-4-oxobutanoyl chloride(122.7 mg, 0.75 mmol, 1.5 equiv.) was added drop wise. After thecomplete addition of 4-(dimethylamino)-4-oxobutanoyl chloride thereaction mixture was slowly warmed up to room temperature and stirredfurther for 4 h. After completion of the reaction solvent was evaporatedand the residue thus obtained was washed with water, filtered and dried.The crude product was purified by flash chromatography (gradient elution10% methanol/EtOAc-20% methanol/EtOAc) to give yellow solid, dried thesolvent by vacuum and added dry DCM (10 mL), filtered by cotton to getcompound JC071 (142.3 mg, 60% yield).

The following compounds were synthesized by procedure H: JC007, JC008,JC009, JC010, JC011, JC053, JC054, JC055, JC056, JC057, JC058, JC059,JC061, JC062, JC063, JC068, JC071, JC072, JC073, JC074, JC075, JC076,JC077, JC078, JC089, JC090, JC091, JC092, JC093, JC101, JC119, JC120,JC129, JC130.

4-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxopiperidin-1-yl)-N,N-dimethyl-4-oxobutanamide (JC071)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (br s, 2H), 7.21 (m, 6H), 4.86 (s, 2H),4.81 (s, 2H), 2.99 (s, 3H), 2.91 (s, 3H), 2.59 (t, J=7.2 Hz, 2H), 2.54(t, J=7.2 Hz, 2H).

¹³C NMR (100 MHz, CDCl₃) δ 186.1, 171.0, 170.0, 150.9 (dd, J_(CF)=252Hz, J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=252 Hz, J_(C—CF)=13 Hz, 2C),136.1, 135.5, 132.1 (dd, J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=3.5 Hz, 2C),131.5, 127.2 (dd, J_(C—C—CF)=6.4 Hz, J_(C—C—CF)=4.2 Hz, 2C), 119.2 (d,J_(C—CF)=17 Hz), 119.0 (d, J_(C—CF)=17 Hz), 118.1 (d, J_(C—CF)=17 Hz),117.8 (d, J_(C—CF)=17 Hz), 46.0, 37.2, 35.7, 29.8, 28.2, 27.8.

3,5-Di((E)-benzylidene)-1-(2-(dimethylamino)ethyl)piperidin-4-one(JC007)

¹H NMR (400 MHz, CDCl₃) δ 7.83 (br s, 2H), 7.39 (m, 10H), 3.91 (br s,4H), 2.71 (t, J=6.8 Hz, 2H), 2.42 (t, J=6.8 Hz, 2H), 2.21 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 187.3, 136.9 (2C), 135.2 (2C), 133.1 (2C),130.4 (2C), 129.1 (2C), 128.6 (2C), 56.7, 54.9, 54.3, 45.3.

Methyl 3-(3,5-di((E)-benzylidene)-4-oxopiperidin-1-yl)propanoate (JC008)

¹H NMR (400 MHz, CDCl₃) δ 7.82 (br s, 2H), 7.38 (m, 10H), 3.86 (br s,4H), 3.59 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H).

¹³C NMR (100 MHz, CDCl₃) δ 187.1, 172.5, 136.8 (2C), 135.2 (2C), 132.9(2C), 130.4 (2C), 129.1 (2C), 128.6 (2C), 54.6, 52.2, 51.7, 32.6.

3,5-Di((E)-benzylidene)-1-(3-oxobutyl)piperidin-4-one (JC009)

¹H NMR (400 MHz, CDCl₃) δ 7.84 (br s, 2H), 7.41 (m, 10H), 3.85 (br s,4H), 2.86 (t, J=7.1 Hz, 2H), 2.57 (t, J=7.1 Hz, 2H), 2.07 (s, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 207.3, 187.0, 136.7 (2C), 135.1 (2C), 133.0(2C), 129.2 (2C), 128.7 (2C), 54.9, 51.5, 41.6, 30.3.

Ethyl 2-(3,5-di((E)-benzylidene)-4-oxopiperidin-1-yl)acetate (JC010)

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 2H), 7.37 (m, 10H), 4.11 (q, J=7.1Hz, 2H), 4.04 (br s, 4H), 3.41 (s, 2H), 1.15 (t, J=7.1 Hz, 3H).

¹³C NMR (100 MHz, CDCl₃) δ 186.9, 170.0, 136.9 (2C), 135.2 (2C), 132.9(2C), 130.4 (2C), 129.1 (2C), 128.6 (2C), 60.7, 57.8, 54.1, 14.1.

Dimethyl 2-(3,5-di((E)-benzylidene)-4-oxopiperidin-1-yl)maleate (JC011)

¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 2H), 7.46 (m, 10H), 4.51 (s, 4H),4.43 (s, 1H), 3.37 (s, 3H), 3.09 (s, 3H).

¹³C NMR (100 MHz, DMSO-d₆) δ 186.0, 166.8, 165.0, 153.7, 137.7 (2C),134.4 (2C), 132.1 (2C), 130.9 (2C), 130.2 (2C), 129.3 (2C), 87.7, 52.4,50.9, 48.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-N-(2-(dimethylamino)ethyl)-4-oxopiperidine-1-carboxamide(JC053)

¹H NMR (400 MHz, CDCl₃) δ 7.68 (br s, 2H), 7.25 (m, 6H), 4.68 (br s,4H), 3.27 (t, J=7.4 Hz, 2H), 2.48 (t, J=7.4 Hz, 2H), 2.23 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 187.2, 156.8, 151.1 (dd, =254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C), 135.3 (2C),132.4 (2C), 131.5 (dd, J_(C—C—CF)=5.6 Hz, J_(C—C—CF)=3.5 Hz, 2C), 127.4(dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=4.2 Hz, 2C), 119.6 (d, J_(C—CF)=17Hz, 2C), 117.9 (d, J_(C—CF)=17 Hz, 2C), 59.7, 44.8, 43.9, 36.3.

3,5-Bis((E)-3,4-difluorobenzylidene)-N,N-dimethyl-4-oxopiperidine-1-carboxamide(JC054)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 2H), 7.21 (m, 6H), 4.43 (br s,4H), 2.67 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 188.4, 163.6, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C),135.1 (2C), 132.7 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.5 Hz, 2C), 126.9(dd, J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=3.5 Hz, 2C), 128.9 (2C), 119.1 (d,J_(C—CF)=17 Hz, 2C), 117.5 (d, J_(C—CF)=17 Hz, 2C), 48.4, 38.1.

3,5-Bis((E)-3,4-difluorobenzylidene)-N-(2-(dimethylamino)ethyl)-N-methyl-4-oxopiperidine-1-carboxamide(JC055)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 2H), 7.22 (m, 6H), 4.43 (br s,4H), 3.21 (t, J=6.7 Hz, 2H), 2.67 (s, 3H), 2.32 (t, J=6.7 Hz, 2H), 2.14(s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.3, 163.6, 151.1 (dd, =254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C), 135.0 (2C),133.0 (2C), 131.8 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.5 Hz, 2C), 127.0(dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.5 Hz, 2C), 118.8 (d, J_(C—CF)=17Hz, 2C), 117.5 (d, J_(C—CF)=17 Hz, 2C), 56.6, 48.5, 47.8, 45.6, 36.3.

3,5-Bis((E)-3,4-difluorobenzylidene)-N-methyl-4-oxo-N-phenylpiperidine-1-carboxamide(JC056)

¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, 2H), 7.2-6.8 (m, 11H), 4.44 (s, 4H),3.16 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 186.0, 160.2, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C),145.7, 135.1, 132.3 (2C), 131.6 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.8Hz, 2C), 129.5, 127.2 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.5 Hz, 2C),125.3 (2C), 124.2, 119.1 (d, J_(C—CF)=17 Hz, 2C), 117.5 (d, J_(C—CF)=17Hz, 2C), 56.6, 48.5, 47.8, 45.6, 36.3.

1-Benzyl-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (JC057)

¹H NMR (400 MHz, CDCl₃) δ 7.71 (br s, 2H), 7.3-7.0 (m, 11H), 3.83 (br s,4H), 3.76 (s, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 187.0, 151.1 (dd, J_(CF)=254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C), 136.9, 134.4(2C), 133.7 (2C), 132.1 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.8 Hz, 2C),128.9, 128.5, 127.6 (2C), 126.9 (dd, J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.8Hz, 2C), 118.9 (d, J_(C—CF)=17 Hz, 2C), 117.6 (d, J_(C—CF)=17 Hz, 2C),61.5, 54.1.

1-(3,5-Bis(trifluoromethyl)benzyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC058)

¹H NMR (400 MHz, CDCl₃) δ 7.78 (br. s, 3H), 7.73 (s, 2H), 7.17 (m, 6H),3.87 (br s, 4H), 3.86 (s, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 186.4, 151.1 (dd, J_(CF)=254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=251 Hz, J_(C—CF)=14 Hz, 2C), 139.9, 135.3(2C), 132.9 (2C), 131.8 (q, J_(C—CF)=33.4 Hz, 2C), 131.7 (dd,J_(C—C—CF)=6.2 Hz, J_(C—C—CF)=3.8 Hz, 2C), 128.7 (2C), 126.9 (dd,J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 123.1 (q, J_(CF)=272 Hz),121.6, 118.7 (d, J_(C—CF)=17 Hz, 2C), 117.6 (d, J_(C—CF)=17 Hz, 2C),59.8, 53.9.

1-(3,4-Difluorobenzyl)-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one(JC059)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 2H), 7.2-7.0 (m, 9H), 3.82 (br s,4H), 3.69 (s, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 186.7, 151.1 (dd, J_(CF)=254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz), 150.2 (dd,J_(CF)=254, J_(C—CF)=14 Hz, 2C), 149.7 (dd, J_(CF)=254, J_(C—CF)=14 Hz),134.7, 134.3, 133.4 (2C), 132.0 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8Hz, 2C), 127.0 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 124.4(dd, J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=3.8 Hz, 2C), 118.8 (d, J_(C—CF)=17Hz, 2C), 117.6 (d, J_(C—CF)=17 Hz, 2C), 117.3 (d, J_(C—CF)=17 Hz), 117.1(d, J_(C—CF)=17 Hz), 60.2, 54.1.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(dimethylglycyl)piperidin-4-one(JC061)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 1H), 7.70 (s, 1H), 7.22 (m, 6H),4.97 (s, 2H), 4.86 (s, 2H), 2.96 (s, 2H), 1.99 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 168.9, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, =254 Hz, J_(C—CF)=14 Hz, 2C), 136.5,135.0, 132.8, 132.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C),127.3 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.9, 119.3 (d,J_(C—CF)=17 Hz), 118.8 (d, J_(C—CF)=17 Hz), 117.9 (d, J_(C—CF)=17 Hz,2C), 63.0, 45.8, 44.9, 43.7.

1-Benzoyl-3,5-bis((E)-3,4-difluorobenzylidene)piperidin-4-one (JC062)

¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 2H), 7.21 (m, 11H), 4.76 (br. s, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 170.5, 151.1 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),134.0, 132.2 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 131.4 (2C),130.3, 128.3, 127.0 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C),126.8, 125.3 (2C), 119.0 (d, J_(C—CF)=18 Hz, 2C), 117.9 (d, J_(C—CF)=18Hz, 2C).

2-(Dimethylamino)ethyl3,5-bis((E)-3,4-difluorobenzylidene)-4-oxopiperidine-1-carboxylate(JC063)

¹H NMR (400 MHz, CDCl₃) δ 7.69 (br s, 2H), 7.23 (m, 6H), 4.73 (br s,4H), 4.13 (t, J=5.7 Hz, 2H), 2.45 (t, J=5.7 Hz, 2H), 2.15 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 155.0, 150.9 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),135.9, 135.4 (2C), 132.3 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C),131.6, 127.1 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 118.9 (d,J_(C—CF)=17 Hz, 2C), 117.9 (d, J_(C—CF)=17 Hz, 2C), 64.2, 57.8, 45.6,45.0.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(dimethylamino)butanoyl)piperidin-4-one(JC068)

¹H NMR (400 MHz, CDCl₃) δ 7.71 (br s, 1H), 7.69 (s, 1H), 7.22 (m, 6H),4.85 (s, 2H), 4.73 (s, 2H), 2.22 (t, J=7.3 Hz, 2H), 2.15 (t, J=7.0 Hz,2H), 2.09 (s, 6H), 1.68 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 171.1, 150.9 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),136.2, 135.3, 132.3 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C),131.5, 127.3 (dd, J_(C—C—CF)=5.8 Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.7,119.3 (d, J_(C—CF)=13.7 Hz), 119.0 (d, J_(C—CF)=14.0 Hz), 118.1 (d,J_(C—CF)=17 Hz), 117.8 (d, J_(C—CF)=17 Hz), 58.6, 46.3, 45.1, 43.1,30.2, 22.8.

1-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxopiperidin-1-yl)-4-(pyrrolidin-1-yl)butane-1,4-dione(JC072)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.69 (s, 1H), 7.21 (m, 6H), 4.86(br s, 2H), 4.80 (s, 2H), 3.41 (m, 4H), 2.54 (m, 4H), 1.92 (m, 2H), 1.81(m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 186.1, 171.0, 170.0, 150.9 (dd, J_(CF)=252Hz, J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=252 Hz, J_(C—CF)=13 Hz, 2C),136.1, 135.5, 132.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C),131.5, 127.2 (dd, J_(C—C—CF)=6.1 Hz, J_(C—C—CF)=3.8 Hz, 2C), 126.9,119.2 (d, J_(C—CF)=17 Hz), 119.0 (d, J_(C—CF)=17 Hz), 118.1 (d,J_(C—CF)=17 Hz), 117.8 (d, J_(C—CF)=17 Hz), 46.5, 46.2, 45.7, 43.2,29.3, 27.4, 26.0, 24.4.

4-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxopiperidin-1-yl)-4-oxobutanoicacid (JC073)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 1H), 7.69 (s, 1H), 7.39 (m, 6H), 4.86(br s, 4H), 2.45 (m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 186.1, 174.2, 170.7, 150.9 (dd, J_(CF)=252Hz, J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=252 Hz, J_(C—CF)=13 Hz, 2C),134.7, 134.6, 133.8, 133.6, 132.4 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2Hz, 2C), 128.5 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 120.0 (d,J_(C—CF)=17 Hz), 119.7 (d, J_(C—CF)=17 Hz), 118.5 (d, J_(C—CF)=17 Hz,2C), 46.6, 42.7, 29.1, 27.5.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(dimethylamino)benzoyl)piperidin-4-one(JC074)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.17 (m, 8H), 6.34 (d, J=8.8Hz, 2H), 4.80 (br s, 4H), 2.91 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 186.6, 171.2, 151.7, 150.9 (dd, J_(CF)=254Hz, J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),135.4 (2C), 132.2, 131.6 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C),129.2, 127.0 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 120.0 (2C),119.0 (d, J_(C—CF)=17 Hz, 2C), 117.8 (d, J_(C—CF)=17 Hz, 2C), 110.6,46.4, 39.9.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(2,2,2-trifluoroacetyl)piperidin-4-one(JC075)

¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.80 (s, 1H), 7.19 (m, 6H), 4.91(s, 2H), 4.82 (s, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 184.4, 155.6 (q, J=37 Hz), 150.9 (dd,J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 137.6, 137.0, 131.0 (dd, J_(C—C—CF)=5.9 Hz,J_(C—C—CF)=4.2 Hz, 2C), 130.5, 127.2 (dd, J_(C—C—CF)=5.9 Hz,J_(C—C—CF)=4.2 Hz, 2C), 126.6, 119.2 (d, J_(C—CF)=17 Hz), 118.8 (d,J_(C—CF)=17 Hz), 118.2 (d, J_(C—CF)=17 Hz), 118.8 (d, J_(C—CF)=17 Hz),116.0 (q, J=288 Hz), 44.6.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-((E)-4-(dimethylamino)but-2-enoyl)piperidin-4-one(JC076)

¹H NMR (400 MHz, CDCl₃) δ 7.72 (br s, 2H), 7.18 (m, 6H), 6.74 (dt,J=15.2, 6.1 Hz, 1H), 6.15 (d, J=15.2 Hz, 1H), 4.84 (br s, 4H), 2.99 (d,J=6.1 Hz, 1H), 2.16 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 185.9, 165.5, 150.9 (dd, =254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C), 143.8, 136.3(2C), 135.2 (2C), 132.3, 131.4, 120.9, 127.0 (2C), 119.2 (d, J_(C—CF)=17Hz, 2C), 118.0 (d, J_(C—CF)=17 Hz, 2C), 60.4, 45.2, 29.7.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-((Z)-4-(dimethylamino)but-2-enoyl)piperidin-4-one(JC077)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.21 (m, 6H), 6.08 (dt,J=11.7, 5.4 Hz, 1H), 5.96 (d, J=11.7 Hz, 1H), 4.89 (s, 2H), 4.74 (s,2H), 3.35 (d, J=5.4 Hz, 2H), 2.27 (s, 6H).

Phenylp-(3,5-bis((E)-3,4-difluorobenzylidene)-4-oxopiperidin-1-yl)-N,N-dimethylphosphonamidate(JC078)

¹H NMR (400 MHz, CDCl₃) δ 7.68 (br s, 2H), 7.11 (m, 6H), 4.42 (br s,4H), 2.58 (s, 3H), 2.56 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 186.0, 150.9 (dd, J_(CF)=254 Hz, J_(C—CF)=14Hz, 2C), 150.8, 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C), 134.6,133.2 (2C), 131.7 (2C), 129.7, 127.0 (2C), 124.6 (2C), 119.7, 119.0 (d,J_(C—CF)=17 Hz, 2C), 117.8 (d, J_(C—CF)=17 Hz, 2C), 46.1, 36.7.

N-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)-4-(dimethylamino)benzamide(JC089)

¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 1H), 8.15 (s, 1H), 7.53 (m, 8H),6.65 (d, J=9.0 Hz, 2H), 4.03 (m, 1H), 3.14 (m, 2H), 2.97 (m, 2H), 2.92(s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 188.1, 166.9, 152.6, 151.0 (dd, =254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),137.7, 132.9 (2C), 132.2 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C),128.4, 127.1 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 120.5 (2C),119.0 (d, J_(C—CF)=17 Hz, 2C), 117.7 (d, J_(C—CF)=17 Hz, 2C), 111.0,44.3, 40.1, 33.9.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(2-(dimethylamino)ethyl)benzoyl)piperidin-4-one(JC090)

¹H NMR (400 MHz, CDCl₃) δ 7.74 (br s, 2H), 7.16 (m, 6H), 7.11 (d, J=8.1Hz, 2H), 6.94 (d, J=8.1 Hz, 2H), 4.77 (br. s, 4H), 2.68 (t, J=8.0 Hz,2H), 2.40 (t, J=8.0 Hz, 2H), 2.29 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 186.2, 170.5, 151.0 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C),143.0, 139.5 (2C), 132.3 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C),131.7, 131.5 (2C), 128.5, 127.0, 126.9 (dd, J_(C—C—CF)=5.9 Hz,J_(C—C—CF)=4.2 Hz, 2C), 119.0 (d, J_(C—CF)=17 Hz, 2C), 117.9 (d,J_(C—CF)=17 Hz, 2C), 60.9, 50.8, 45.1, 33.9.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-methylpiperazine-1-carbonyl)piperidin-4-one(JC091)

¹H NMR (400 MHz, CDCl₃) δ 7.73 (br s, 2H), 7.20 (m, 6H), 4.44 (br s,4H), 3.12 (t, J=8.0 Hz, 4H), 2.16 (s, 3H), 2.11 (t, J=8.0 Hz, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 186.2, 162.8, 151.0 (dd, =254 Hz, J_(C—CF)=14Hz, 2C), 150.4 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C), 135.4 (2C),132.8 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 131.6 (2C), 127.0(dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 119.1 (d, J_(C—CF)=17Hz, 2C), 118.0 (d, J_(C—CF)=17 Hz, 2C), 54.4, 48.4, 46.3, 45.9.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-(4-fluorophenyl)piperazine-1-carbonyl)piperidin-4-one(JC092)

¹H NMR (400 MHz, CDCl₃) δ 7.75 (br s, 2H), 7.24 (m, 4H), 7.16 (m, 2H),6.94 (m, 2H), 6.72 (m, 2H), 4.49 (br s, 4H), 3.24 (m, 4H), 2.76 (m, 4H).

¹³C NMR (100 MHz, CDCl₃) δ 186.1, 162.7, 157.5 (dd, J_(CF)=254 Hz,J_(C—CF)=14 Hz), 151.0 (dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C), 150.4(dd, J_(CF)=254 Hz, J_(C—CF)=14 Hz, 2C), 147.5, 135.4 (2C), 132.8 (dd,J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 131.6 (2C), 127.0 (dd,J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=4.2 Hz, 2C), 119.1 (d, J_(C—CF)=17 Hz,2C), 118.4 (d, J_(C—CF)=7.8 Hz), 117.9 (d, J_(C—CF)=17 Hz, 2C), 115.7(d, J_(C—CF)=22 Hz), 50.0, 48.3, 46.5.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(4-oxopiperidine-1-carbonyl)piperidin-4-one(JC093)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.21 (m, 6H), 4.53 (br s,4H), 3.37 (m, 4H), 2.25 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 206.7, 185.9, 162.6, 151.0 (dd, J_(CF)=255Hz, J_(C—CF)=13 Hz, 2C), 150.3 (dd, J_(CF)=251 Hz, J_(C—CF)=13 Hz, 2C),135.7 (2C), 132.4 (2C), 131.4 (dd, J_(C—C—CF)=5.5 Hz, J_(C—C—CF)=4.2 Hz,2C), 127.0 (dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.5 Hz, 2C), 119.1 (d,J_(C—CF)=18 Hz, 2C), 118.0 (d, J_(C—CF)=17 Hz, 2C), 50.9, 48.4, 45.9,40.8.

3,5-Bis((E)-3,4-difluorobenzylidene)-1-(1-methylpyrrolidine-3-carbonyl)piperidin-4-one(JC101)

¹H NMR (500 MHz, CDCl₃) δ 7.76 (s, 1H), 7.71 (s, 1H), 7.17 (m, 6H), 4.76(br s, 4H), 3.20 (m, 1H), 2.95 (m, 1H), 2.88 (m, 1H), 2.69 (m, 1H), 2.45(m, 1H), 2.40 (s, 3H), 1.91 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 185.7, 172.6, 151.2 (dd, J_(CF)=255 Hz,J_(C—CF)=14 Hz, 2C), 150.5 (dd, =255 Hz, J_(C—CF)=13 Hz, 2C), 136.5,135.7, 132.0 (2C), 131.5 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.4 Hz),131.0 (dd, J_(C—C—CF)=6.0 Hz, J_(C—C—CF)=3.8 Hz), 127.2 (d,J_(C—C—CF)=6.1 Hz), 126.8 (d, J_(C—C—CF)=5.5 Hz), 119.2 (d, J_(C—CF)=18Hz), 118.9 (d, J_(C—CF)=18 Hz), 118.2 (d, J_(C—CF)=18 Hz), 117.9 (d,J_(C—CF)=18 Hz), 58.4, 55.4, 46.2, 43.5, 41.3, 40.1, 28.6.

1-(2,6-Bis((E)-3,4-difluorobenzylidene)-1,1-dioxidothiomorpholino)-3-(diethylamino)propan-1-one(JC119)

¹H NMR (300 MHz, CDCl₃) δ 7.61 (s, 1H), 7.54 (s, 1H), 7.46 (m, 2H), 7.28(m, 4H), 4.94 (s, 2H), 4.90 (s, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.50 (q,J=7.1 Hz, 4H), 2.35 (t, J=7.4 Hz, 2H), 1.03 (t, J=7.1 Hz, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 170.5, 151.4 (dd, J_(CF)=255 Hz, J_(C—CF)=10Hz, 2C), 150.5 (dd, J_(CF)=251 Hz, J_(C—CF)=13 Hz, 2C), 137.6, 137.1,133.1, 132.8, 129.1, 128.9, 126.5, 126.0, 118.7 (d, J_(C—CF)=18 Hz),118.6 (d, J_(C—CF)=17 Hz), 118.4 (d, J_(C—CF)=18 Hz), 118.2 (d,J_(C—CF)=18 Hz), 48.2, 46.7, 45.4, 42.2, 30.2, 10.7.

1-(2,6-Bis((E)-3,4-difluorobenzylidene)-1,1-dioxidothiomorpholino)-3-(piperidin-1-yl)propan-1-one(JC120)

¹H NMR (300 MHz, CDCl₃) δ 7.61 (s, 1H), 7.53 (s, 1H), 7.51 (m, 2H), 7.28(m, 4H), 4.93 (s, 2H), 4.86 (s, 2H), 2.55 (t, J=6.4 Hz, 2H), 2.19 (m,4H), 1.56 (m, 4H), 1.43 (t, J=6.4 Hz, 2H), 1.28 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 170.8, 151.5 (dd, =255 Hz, J_(C—CF)=11 Hz,2C), 150.4 (dd, J_(CF)=253 Hz, J_(C—CF)=13 Hz, 2C), 138.2, 137.2, 133.1,132.5, 129.2, 128.9, 126.4, 125.9, 118.8 (d, J_(C—CF)=18 Hz), 118.5 (d,J_(C—CF)=16 Hz), 118.4 (d, J_(C—CF)=16 Hz), 118.1 (d, J_(C—CF)=18 Hz),54.2, 53.9, 45.2, 42.1, 30.6, 25.6, 23.9.

2-(3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxopiperidin-1-yl)-2-oxoethylmorpholine-4-carbodithioate (JC129)

¹H NMR (500 MHz, CDCl₃) δ 7.75 (s, 1H), 7.70 (s, 1H), 7.21 (m, 6H), 4.90(s, 2H), 4.87 (s, 2H), 4.18 (m, 4H), 1.87 (s, 2H), 3.71 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 195.0, 185.6, 166.4, 151.0 (dm, J_(CF)=248Hz, 2C), 150.4 (dm, J_(CF)=248 Hz, 2C), 136.2, 135.7, 131.7 (d,J_(C—C—CF)=6.7 Hz), 131.2 (dm, J_(C—C—CF)=6.7 Hz), 127.0 (dd,J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.4 Hz, 2C), 126.9, 119.2 (d, J_(C—CF)=17Hz), 118.9 (d, J_(C—CF)=17 Hz), 118.0 (dm, J_(C—CF)=17 Hz), 117.8 (d,J_(C—CF)=17 Hz), 46.9, 43.6, 39.1, 29.6.

2-((3,5-Bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexyl)amino)-2-oxoethylmorpholine-4-carbodithioate (JC130)

¹H NMR (400 MHz, CDCl₃) δ 7.76 (br s, 2H), 7.17 (m, 6H), 4.28 (m, 3H),3.85 (m, 4H), 3.74 (m, 4H), 3.04 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 195.8, 187.5, 168.4, 151.0 (dd, J_(CF)=248Hz, J_(C—CF)=13 Hz, 2C), 150.4 (dd, J_(CF)=248 Hz, J_(C—CF)=13 Hz, 2C),137.9 (2C), 132.4 (2C), 132.0 (dd, J_(C—C—CF)=5.9 Hz, J_(C—C—CF)=3.6 Hz,2C), 127.0 (dd, J_(C—C—CF)=6.3 Hz, J_(C—C—CF)=3.8 Hz, 2C), 118.8 (d, =17Hz, 2C), 117.5 (d, =17 Hz, 2C), 65.9 (b, 1C), 51.5 (b, 1C), 44.3, 39.0,32.8.

Example 2: Biological Data

It was identified that compounds JC001, JC018, JC018, JC021, JC022,JC026, JC028, JC032, JC048, JC049, JC060, JC070, JC072, JC081, and JC094significantly inhibited Wnt/β-catenin-mediated transcription (FIGS. 5A,B and 6A-C). JC001, JC026, JC049, JC060, JC070, JC081, JC082, JC094,JC098, and JC099. were chosen for mouse xenograft studies of human coloncancer (FIGS. 7A-D, 8A-C, and 9A-C). It was found that JC026, JC049,JC060, JC081, JC082, JC094, and JC099 significantly inhibited the tumorgrowth of which JC049 showed the strongest inhibition (FIG. 7A-C). JC070also showed some inhibition, but did not reach significance probably dueto small sample size. At the end of the experiments, the mice weresacrificed and tumor weights were measured, confirming that thesecompounds significantly inhibited tumor growth. Finally, it was foundthat these compounds did not affect mouse body weight (FIG. 7D).

General Protocol for Cell Culture and Lentiviral Infection

293T cells were maintained in DMEM medium containing 10% FBS andantibiotics (penicillin and streptomycin) at 37° C. in 5% CO₂. Cellswere stably infected with lentiviruses expressing the TopFlash reporter(293T/Top cells). The β-catenin mutant (β-cat*, the constitutivelyactive mutant) construct was prepared using the retroviral expressionvector by standard PCR. For viral transduction, retrovirus was obtainedby co-trasfection of pQCXIP-β-cat* with packaging plasmids into 293Tcells following the manufacturer's instructions. 293T/Top stable cellswere seeded in 10 cm dish and incubated overnight. The next day cellswere treated with retroviral particles. After 12 hours, the medium wasreplaced with fresh medium. 2 days post virus infection, the cells wereselected with puromycin for 5 days to generate the 293T/Top/β-cat*stable cell line.

General Protocol for TCF-Luciferase Activity Assay

293T/Top/β-cat* cells were plated at 40%-50% confluences in 12-wellplate for 8 hours and then treated with Wnt inhibitors overnight. Theluciferase activity of total cell lysates was measured using LuciferaseAssay System (Promega). The related TCF-luciferase activity wasnormalized against the protein concentration of each cell lysate sample.

Mouse Xenografts

5×10⁵ of SW480 cells were injected subcutaneously into the flank area of6-8-week-old nude mice. Tumor volume was measured by using an electroniccaliper and calculated with the formula length×width²×0.5, every 2 days.12 days after inoculation, tumor bearing mice were administered Wntinhibitors (dissolved in 10% DMSO+20% Cremophor EL+70% normal saline)via intraperitoneal injection for 5 days per week for 10 days at 10mg/kg. Animal body weights were measured before drug treatments and atthe end of the experiments. At the end of the experiments, animals wereeuthanized with carbon dioxide, followed by cervical dislocation. Thetumors were dissected and weighed on the digital balance. We housed micein pathogen-free facilities under 12-h light and 12-h dark cycle. Theanimal protocol and experimental procedures were approved by theDivision of Laboratory Animal Medicine of UCLA and were in accordancewith the US National Institute of Health guidelines.

General Protocol for Isolation of Cancer Stem Cells and Tumor-SphereFormation Assays

For the identification of ALDH⁺HCT116 cancer stem cells, HCT116 cellswere trypsinized to single cells and subsequently stained withanti-ALDEFLUOR kits (Stem Cell Technologies) following themanufacturer's guidelines to label the ALDH⁺ populations.

To isolate ALDH⁺MDA-MB-231 breast cancer stem cells, MDA-MB-231 cellswere trypsinized to single cells and subsequently stained withanti-ALDEFLUOR kits (Stem Cell Technologies) following themanufacturer's guidelines to label the ALDH⁺ populations. ALDH⁺subpopulations were separated by a FACSVantage SE cell sorter (BecktonDickson).

To isolate ALDH⁺CD44^(high)SCC1 cancer stem cells, SCC1 cells weretrypsinized to single cells and subsequently stained with anti-ALDEFLUORkits and then incubated with anti-CD44-APC (BD PharMingen Cat #559942)for 30 min on ice. ALDH⁺CD44^(high)SCC1 cells were sorted by aFACSVantage SE cell sorter.

To isolate CD13^(high)CD133^(high)Hep3B liver cancer stem cells, Hep3Bcells were trypsinized to single cells and stained with anti-CD13-APC(Miltenyi Biotec, Cat #130-103-669) and anti-CD133-PE (Miltenyi Biotec,Cat #130-098-826) antibody for 30 min on ice.CD13^(high)CD133^(high)Hep3B cells were sorted by a FACSVantage SE cellsorter.

For the tumorsphere formation assay, the sorted single cells were platedon ultralow attachment six-well plates (Corning) at a density of 25,000viable cells per well for cancer stem cells. Cells were grown in aserum-free mammary epithelial basal medium (MEBM; Lonza), supplementedwith B27 (Invitrogen), 20 ng/ml EGF (R&D Systems), 10 ng/ml FGF (R&DSystems), 4 mg/ml Gentamycin (Invitrogen), 1 ng/ml Hydrocortisone(Sigma-Aldrich), 5 mg/ml Insulin, 100 nM of beta-mercaptoethanol(Sigma-Aldrich) and 250 nM of Wnt inhibitors as indicated. Tumorsphereswere observed under the microscope 2 weeks later.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

1. A compound of Formula I, Formula II, Formula III:

or a pharmaceutically acceptable salt thereof, wherein, X is C═O, NR³,C═NR³, S, S═O, S(═O)₂, or C═S; Y is heteroaryl, aryl, or C(O)N(R⁷)(R⁴);R¹ and R² are independently selected from aryl, heteroaryl, andheterocyclyl; R⁴ is hydrogen, alkyl, alkenyl, acyl, aryl, heteroaryl,C(O)aryl, C(O)alkyl, C(O)Oalkyl, C(O)Oaryl, C(O)Oheteroaryl,C(O)N(R^(5a)R^(5b)), aralkyl, alkylsulfonyl, or

R^(5a) and R^(5b) are independently selected from H, alkyl, aralkyl, andaryl; R⁶ is H, alkyl, or aryl; and R³ and R⁷ are each independently H oralkyl.
 2. The compound of claim 1, wherein R¹ and R² are independentlyselected from aryl or heteroaryl. 3-11. (canceled)
 12. The compound ofclaim 2, wherein the compound is represented by Formula I or Formula IIor a pharmaceutically acceptable salt thereof:

wherein, X is C═O, NR³, C═NR³, S, S═O, S(═O)₂, or C═S; R¹ and R² areindependently selected from aryl or heteroaryl; R⁴ is alkyl, alkenyl,acyl, C(O)aryl, C(O)alkyl, C(O)Oalkyl, C(O)Oaryl, C(O)Oheteroaryl,C(O)N(R^(5a)R^(5b)), aralkyl, alkylsulfonyl, or

R^(5a) and R^(5b) are independently selected from H, alkyl, aralkyl, andaryl; R⁶ is H, alkyl, or aryl; and R³ and R⁷ are each independently H oralkyl.
 13. (canceled)
 14. The compound of claim 1, wherein the compoundis represented by Formula Ib, Ic, Id, IIb, IIc, or IId:

or a pharmaceutically acceptable salt thereof. 15-17. (canceled)
 18. Thecompound of claim 14, wherein R⁴ is C(O)N(R^(5a)R^(5b)) or

19-23. (canceled)
 24. The compound of claim 18, wherein R^(5a) is alkyl,further substituted with hydroxyl or amino. 25-28. (canceled)
 29. Thecompound of claim 14, wherein R⁴ is alkyl, alkenyl, acyl, C(O)alkyl,C(O)Oalkyl, aralkyl, or alkylsulfonyl.
 30. The compound of claim 29,wherein R⁴ is further substituted with at least one basic aminosubstituent. 31-33. (canceled)
 34. The compound of claim 14, wherein R⁴is further substituted with at least one substituent selected fromC(O)Oalkyl, C(O)alkyl, alkenyl, thio, alkenyl, carboxyl, amido, andalkyloxy. 35-46. (canceled)
 47. The compound of claim 14, wherein thecompound is represented by Formula IIe:

wherein R⁷ is H or alkyl; and R⁸ is aminoalkyl or aryl. 48-51.(canceled)
 52. The compound of claim 1, wherein the compound isrepresented by Formula III:

or a pharmaceutically acceptable salt thereof.
 53. (canceled)
 54. Thecompound of claim 52, wherein Y is aryl substituted with at least onebasic amino substituent. 55-60. (canceled)
 61. The compound of claim 5,wherein the aryl of Y is further substituted with at least onesubstituent selected from C(O)Oalkyl, C(O)alkyl, alkenyl thio, alkenyl,carboxyl, amido, and alkyloxy.
 62. The compound of claim 52, wherein Yis C(O)N(R⁷)(R⁴).
 63. (canceled)
 64. (canceled)
 65. The compound ofclaim 62, wherein R⁴ is aryl.
 66. The compound of claim 65, wherein thearyl of R⁴ is further substituted, with at least one basic aminosubstituent. 67-73. (canceled)
 74. The compound of claim 1, wherein thecompound is selected from:

or a pharmaceutically acceptable salt thereof.
 75. (canceled) 76.(canceled)
 77. A pharmaceutical composition comprising the compound ofclaim 1 and a pharmaceutically acceptable excipient.
 78. A method ofinhibiting β-catenin or a variant thereof, comprising administering to asubject a compound of claim
 1. 79-82. (canceled)
 83. A method oftreating cancer, comprising administering to a subject in need of atreatment for cancer a compound of claim
 1. 84. (canceled) 85.(canceled)